123,836 results on '"Cytotoxic T cell"'
Search Results
2. Polo-like kinase 1 regulates immune synapse assembly and cytotoxic T cell function by driving microtubule dynamics.
- Author
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Zevolini, Fabrizia, Onnis, Anna, Khazen, Roxana, Müller, Sabina, Marotta, Giuseppe, Valitutti, Salvatore, Finetti, Francesca, and Baldari, Cosima T.
- Subjects
- *
CYTOTOXIC T cells , *CELL physiology , *MICROTUBULES , *SYNAPSES , *AURORA kinases , *GRANULE cells - Abstract
Elimination of virally infected or tumoral cells is mediated by cytotoxic T cells (CTL). Upon antigen recognition, CTLs assemble a specialized signaling and secretory domain at the interface with their target, the immune synapse (IS). During IS formation, CTLs acquire a transient polarity, marked by re-orientation of the centrosome and microtubule cytoskeleton toward the IS, thus directing the transport and delivery of the lytic granules to the target cell. Based on the implication that the kinase Aurora A has a role in CTL function, we hypothesized that its substrate, the mitotic regulator Polo-like kinase 1 (PLK1), might participate in CTL IS assembly. We demonstrate that PLK1 is phosphorylated upon TCR triggering and polarizes to the IS. PLK1 silencing or inhibition results in impaired IS assembly and function, as witnessed by defective synaptic accumulation of T cell receptors (TCRs), as well as compromised centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing. This function is achieved by coupling early signaling to microtubule dynamics, a function pivotal for CTL-mediated cytotoxicity. These results identify PLK1 as a new player in CTL IS assembly and function. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
3. Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKTtriggered dendritic cells in situ.
- Author
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Satoru Yamasaki, Kanako Shimizu, and Shin-ichiro Fujii
- Subjects
PROSTATE cancer ,DENDRITIC cells ,TUMOR antigens ,METASTASIS ,ANTIGENS ,CANCER vaccines ,SPREADING cortical depression - Abstract
Introduction: Cancer is categorized into two types based on the microenvironment: cold and hot tumors. The former is challenging to stimulate through immunity. The immunogenicity of cancer relies on the quality and quantity of cancer antigens, whether recognized by T cells or not. Successful cancer immunotherapy hinges on the cancer cell type, antigenicity and subsequent immune reactions. The T cell response is particularly crucial for secondary epitope spreading, although the factors affecting these mechanisms remain unknown. Prostate cancer often becomes resistant to standard therapy despite identifying several antigens, placing it among immunologically cold tumors. We aim to leverage prostate cancer antigens to investigate the potential induction of epitope spreading in cold tumors. This study specifically focuses on identifying factors involved in secondary epitope spreading based on artificial adjuvant vector cell (aAVC) therapy, a method established as invariant natural killer T (iNKT) -licensed DC therapy. Methods: We concentrated on three prostate cancer antigens (prostatespecific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP)). By introducing allogeneic cells with the antigen and murine CD1d mRNA, followed by a-galactosylceramide (a-GalCer) loading, we generated five types of aAVCs, i.e, monovalent, divalent and trivalent antigen-expressing aAVCs and four types of prostate antigenexpressing cold tumors. We evaluated iNKT activation and antigen-specific CD8+ T cell responses against tumor cells prompted by the aAVCs. Results: Our study revealed that monovalent aAVCs, expressing a single prostate antigen, primed T cells for primary tumor antigens and also induced T cells targeting additional tumor antigens by triggering a tumor antigen-spreading response. When we investigated the immune response by trivalent aAVC (aAVC-PROS), aAVC-PROS therapy elicited multiple antigenspecific CD8+ T cells simultaneously. These CD8+ T cells exhibited both preventive and therapeutic effects against tumor progression. Conclusions: The findings from this study highlight the promising role of tumor antigen-expressing aAVCs, in inducing efficient epitope spreading and generating robust immune responses against cancer. Our results also propose that multivalent antigen-expressing aAVCs present a promising therapeutic option and could be a more comprehensive therapy for treating cold tumors like prostate cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
4. Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer.
- Author
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Vojdani, Aristo, Koksoy, Sadi, Vojdani, Elroy, Engelman, Mark, Benzvi, Carina, and Lerner, Aaron
- Subjects
CYTOTOXIC T cells ,KILLER cells ,T cells ,IMMUNE system ,HEALING - Abstract
Natural killer (NK) cells and cytotoxic T (CD8
+ ) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8+ cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8+ T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56+ CD16dim , CD56dim CD16+ , CD57+ , and CD57+ CD16+ NK cells, the NKT, CD57+ CD8+ , and KIR+ CD8+ T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8+ T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied. [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
5. Cytotoxic T lymphocytes require transcription for infiltration but not target cell lysis.
- Author
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Richard, Arianne C, Ma, Claire Y, Marioni, John C, and Griffiths, Gillian M
- Abstract
Effector cytotoxic T lymphocytes (CTLs) are critical for ridding the body of infected or cancerous cells. CTL T cell receptor (TCR) ligation not only drives the delivery and release of cytolytic granules but also initiates a new wave of transcription. In order to address whether TCR‐induced transcriptomic changes impact the ability of CTLs to kill, we asked which genes are expressed immediately after CTLs encounter targets and how CTL responses change when inhibiting transcription. Our data demonstrate that while expression of cytokines/chemokines and transcriptional machinery depend on transcription, cytotoxic protein expression and cytolytic activity are relatively robust to transcription blockade, with CTLs lysing nearby target cells for several hours after actinomycin D treatment. Monitoring CTL movement among target cells after inhibiting transcription demonstrates an infiltration defect that is not rectified by provision of exogenous cytokine/chemokine gradients, indicating a cell‐intrinsic transcriptional requirement for infiltration. Together, our results reveal differential molecular control of CTL functions, separating recruitment and infiltration from cytolysis. Synopsis: Cytotoxic T lymphocytes initiate de novo transcription immediately after target encounter. While already primed for cytolysis, these transcriptomic changes enable cytokine/chemokine expression and infiltration between target cells, revealing differential molecular controls for cytolysis and recruitment. Target cell recognition triggers rapid transcriptomic changes in CTLs.Messenger RNAs for cytokines/chemokines but not for cytolytic proteins are upregulated.Inhibition of de novo transcription blocks CTL infiltration and this cannot be rectified by exogenous cytokines/chemokines.While CTLs are pre‐armed for cytolysis, they require de novo transcription to migrate between targets. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
6. NFIL3 contributes to cytotoxic T lymphocyte-mediated killing
- Author
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Tiphaine Douanne, Katharina Strege, Martin Del Castillo Velasco-Herrera, Adam M. Rochussen, David J. Adams, and Gillian M. Griffiths
- Subjects
NFIL3 ,cytotoxic T cell ,T-cell-mediated killing ,perforin ,granzyme ,autoimmunity ,Biology (General) ,QH301-705.5 - Abstract
Cytotoxic T lymphocytes (CTLs) are key effectors of the adaptive immune system that recognize and eliminate virally infected and cancerous cells. In naive CD8+ T cells, T-cell receptor (TCR) engagement drives a number of transcriptional, translational and proliferation changes over the course of hours and days leading to differentiation into CTLs. To gain a better insight into this mechanism, we compared the transcriptional profiles of naive CD8+ T cells to those of activated CTLs. To find new regulators of CTL function, we performed a selective clustered regularly interspaced short palindromic repeats (CRISPR) screen on upregulated genes and identified nuclear factor IL-3 (NFIL3) as a potential regulator of cytotoxicity. Although NFIL3 has established roles in several immune cells including natural killer, Treg, dendritic and CD4+ T cells, its function in CD8+ CTLs is less well understood. Using CRISPR/Cas9 editing, we found that removing NFIL3 in CTLs resulted in a marked decrease in cytotoxicity. We found that in CTLs lacking NFIL3 TCR-induced extracellular signal-regulated kinase phosphorylation, immune synapse formation and granule release were all intact while cytotoxicity was functionally impaired in vitro. Strikingly, NFIL3 controls the production of cytolytic proteins as well as effector cytokines. Thus, NFIL3 plays a cell intrinsic role in modulating cytolytic mechanisms in CTLs.
- Published
- 2024
- Full Text
- View/download PDF
7. Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ
- Author
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Satoru Yamasaki, Kanako Shimizu, and Shin-ichiro Fujii
- Subjects
cancer ,cytotoxic T cell ,dendritic cell ,immunotherapy ,iNKT cell ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionCancer is categorized into two types based on the microenvironment: cold and hot tumors. The former is challenging to stimulate through immunity. The immunogenicity of cancer relies on the quality and quantity of cancer antigens, whether recognized by T cells or not. Successful cancer immunotherapy hinges on the cancer cell type, antigenicity and subsequent immune reactions. The T cell response is particularly crucial for secondary epitope spreading, although the factors affecting these mechanisms remain unknown. Prostate cancer often becomes resistant to standard therapy despite identifying several antigens, placing it among immunologically cold tumors. We aim to leverage prostate cancer antigens to investigate the potential induction of epitope spreading in cold tumors. This study specifically focuses on identifying factors involved in secondary epitope spreading based on artificial adjuvant vector cell (aAVC) therapy, a method established as invariant natural killer T (iNKT) -licensed DC therapy.MethodsWe concentrated on three prostate cancer antigens (prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP)). By introducing allogeneic cells with the antigen and murine CD1d mRNA, followed by α-galactosylceramide (α-GalCer) loading, we generated five types of aAVCs, i.e, monovalent, divalent and trivalent antigen-expressing aAVCs and four types of prostate antigen-expressing cold tumors. We evaluated iNKT activation and antigen-specific CD8+ T cell responses against tumor cells prompted by the aAVCs.ResultsOur study revealed that monovalent aAVCs, expressing a single prostate antigen, primed T cells for primary tumor antigens and also induced T cells targeting additional tumor antigens by triggering a tumor antigen-spreading response. When we investigated the immune response by trivalent aAVC (aAVC-PROS), aAVC-PROS therapy elicited multiple antigen-specific CD8+ T cells simultaneously. These CD8+ T cells exhibited both preventive and therapeutic effects against tumor progression.ConclusionsThe findings from this study highlight the promising role of tumor antigen-expressing aAVCs, in inducing efficient epitope spreading and generating robust immune responses against cancer. Our results also propose that multivalent antigen-expressing aAVCs present a promising therapeutic option and could be a more comprehensive therapy for treating cold tumors like prostate cancer.
- Published
- 2024
- Full Text
- View/download PDF
8. Autophagy induced macrophages by α-alumina(α-AL2O3) conjugated cysteine peptidase, enhances the cytotoxic activity of CD8+ T lymphocytes against Leishmania major
- Author
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Fatemeh Beyzay, Ahamad Zavaran Hosseini, Ali Hazrati, Mozhdeh Karimi, and Sara Soudi
- Subjects
leishmania major ,cysteine peptidase ,α-alumina ,autophagy ,cytotoxic t cell ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Introduction: Induction of a protective immune response against Leishmania major requires the activation of both TH1 and CD8+ T lymphocytes. Because L. major is an intra-phagosomal parasite, its antigens do not have access to MHC-I. The present study aimed to evaluate the effect of cysteine peptidase A (CPA)/cysteine peptidase B (CPB) conjugated to α-AL2O3 on autophagy induction in L. major infected macrophages and subsequent activation of cytotoxic CD8+ T lymphocytes. Methods: Recombinant CPA and CPB of L. major were produced in expression vectors and purified. Aldehyde functionalized α-AL2O3 were conjugated to hydrazine-modified CPA/CPB by a chemical bond was confirmed by Fourier-transform infrared spectroscopy (FTIR). The High efficient internalization of α-AL2O3 conjugated CPA/CPB to macrophages was confirmed using a fluorescence microscope and flowcytometry. Induction of the acidic autophagosome and LC3 conversion in macrophages was determined by acridine orange (AO) staining and western blot. Autophagy-activated macrophages were used for CD8+ T cell priming. Cytotoxic activity of the primed CD8+ T cell against L. major infected macrophages was measured using apoptosis assay. Results: α-AL2O3 conjugated CPA/CPB enhances macrophages antigen uptake and increases acidic vacuole formation and LC-3I to LC-3II conversion. Co-culture of autophagy-activated macrophages with CD8+ T cells augmented CD8+ T cells priming and proliferation more than in other study groups. These primed CD8+ T cells induce significant apoptotic death of L. major infected macrophages compared with non-primed CD8+ T cells. Conclusion: α-AL2O3 nanoparticles enhance the cross-presentation of L. major antigens to CD8+ T cells by inducing autophagy. This finding supports the positive role of autophagy and encourages the use of α-AL2O3 in vaccine design.
- Published
- 2023
- Full Text
- View/download PDF
9. Mitochondrial regulation of CD8+ T cell cytotoxicity
- Author
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Lisci, Miriam and Griffiths, Gillian
- Subjects
CTL ,cytotoxic T lymphocyte ,CD8+ T cell ,mitochondria ,USP30 ,mitochondrial translation ,CD8 T cell ,cytotoxic T cell ,mitochondria lymphocyte ,mitochondria T cell - Abstract
Recent discoveries in the field of immunometabolism have emphasised the importance of mitochondria in the context of T cell development, differentiation, signalling and exhaustion. However, the question of whether mitochondria can actively participate to the killing activity of differentiated, cytotoxic CD8+ T cells (CTLs) remains unanswered. In this work I analyse CTLs derived from USP30-deficient mice, which have been previously characterised as part of the Infection, Immunity and Immunophenotype Consortium and shown to display altered CTL killing. USP30 is a deubiquitinase localised on the outer mitochondrial membrane and on the peroxisomal membrane, where it counteracts mitophagy and pexophagy by cleaving ubiquitin chains from target proteins. Here I characterise T cell motility, signalling, energy requirements and cytotoxicity in CD8+ T cells derived from splenocytes of Usp30-/- mice. Furthermore, I test different mitochondrial functions using both genetic and pharmacological manipulation of oxidative phosphorylation, mitochondrial calcium flux and mitochondrial translation. I highlight mitochondrial translation as a previously uncharacterised mitochondrial function that allows for optimal CTL cytotoxicity. Specifically, I show that both Usp30-/- CTLs and CTLs in which mitochondrial translation is inhibited display impaired cytosolic protein synthesis, which results in lower abundance of cytolytic molecules essential for killing. This requirement was especially evident when CTLs were limiting in numbers or when they needed to sustain killing for prolonged time, underscoring the importance of efficient mitochondrial translation during an immune challenge. Finally, I investigate mechanisms that could link mitochondrial translation to a loss of cytosolic protein synthesis, including mTOR signalling, mitochondrial reactive oxygen species generation and the integrated stress response. Overall, this work uncovers a novel role for mitochondrial translation in CTL cytotoxicity and adds to the growing body of evidence revealing the multifaceted and crucial roles of mitochondria in T cell function.
- Published
- 2021
- Full Text
- View/download PDF
10. Autophagy induced macrophages by a-alumina(a-AL2O3) conjugated cysteine peptidase, enhances the cytotoxic activity of CD8+ T lymphocytes against Leishmania major.
- Author
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Beyzay, Fatemeh, Hosseini, Ahmad Zavaran, Hazrati, Ali, Karimi, Mozhdeh, and Soudi, Sara
- Subjects
- *
T cells , *LEISHMANIA major , *CYTOTOXIC T cells , *MACROPHAGES , *AUTOPHAGY , *CYTOTOXIC T lymphocyte-associated molecule-4 , *PEPTIDASE - Abstract
Introduction: Induction of a protective immune response against Leishmania major requires the activation of both TH1 and CD8+ T lymphocytes. Because L. major is an intra-phagosomal parasite, its antigens do not have access to MHC-I. The present study aimed to evaluate the effect of cysteine peptidase A (CPA)/cysteine peptidase B (CPB) conjugated to α-AL2O3 on autophagy induction in L. major infected macrophages and subsequent activation of cytotoxic CD8+ T lymphocytes. Methods: Recombinant CPA and CPB of L. major were produced in expression vectors and purified. Aldehyde functionalized α-AL2O3 were conjugated to hydrazine-modified CPA/CPB by a chemical bond was confirmed by Fourier-transform infrared spectroscopy (FTIR). The High efficient internalization of α-AL2O3 conjugated CPA/CPB to macrophages was confirmed using a fluorescence microscope and flowcytometry. Induction of the acidic autophagosome and LC3 conversion in macrophages was determined by acridine orange (AO) staining and western blot. Autophagy-activated macrophages were used for CD8+ T cell priming. Cytotoxic activity of the primed CD8+ T cell against L. major infected macrophages was measured using apoptosis assay. Results: α-AL2O3 conjugated CPA/CPB enhances macrophages antigen uptake and increases acidic vacuole formation and LC-3I to LC-3II conversion. Co-culture of autophagy-activated macrophages with CD8+ T cells augmented CD8+ T cells priming and proliferation more than in other study groups. These primed CD8+ T cells induce significant apoptotic death of L. major infected macrophages compared with non-primed CD8+ T cells. Conclusion: α-AL2O3 nanoparticles enhance the cross-presentation of L. major antigens to CD8+ T cells by inducing autophagy. This finding supports the positive role of autophagy and encourages the use of α-AL2O3 in vaccine design. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
11. Heterogeneity of memory T cells in aging.
- Author
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Jain, Abhinav, Sturmlechner, Ines, Weyand, Cornelia M., and Goronzy, Jörg J.
- Subjects
IMMUNOLOGIC memory ,CELLULAR aging ,BIOLOGICAL systems ,HOMEOSTASIS ,T cells - Abstract
Immune memory is a requisite and remarkable property of the immune system and is the biological foundation of the success of vaccinations in reducing morbidity from infectious diseases. Some vaccines and infections induce longlasting protection, but immunity to other vaccines and particularly in older adults rarely persists over long time periods. Failed induction of an immune response and accelerated waning of immune memory both contribute to the immunocompromised state of the older population. Here we review how T cell memory is influenced by age. T cell memory is maintained by a dynamic population of T cells that are heterogeneous in their kinetic parameters under homeostatic condition and their function. Durability of T cell memory can be influenced not only by the loss of a clonal progeny, but also by broader changes in the composition of functional states and transition of T cells to a dysfunctional state. Genome-wide single cell studies on total T cells have started to provide insights on the influence of age on cell heterogeneity over time. The most striking findings were a trend to progressive effector differentiation and the activation of pro-inflammatory pathways, including the emergence of CD4+ and CD8+ cytotoxic subsets. Genome-wide data on antigen-specific memory T cells are currently limited but can be expected to provide insights on how changes in T cell subset heterogeneity and transcriptome relate to durability of immune protection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
12. Temporal Dynamics of Serum Perforin and Granzyme during the Acute Phase of SARS-CoV-2 Infection.
- Author
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Rahman, MD Tazikur, Ryu, Sukhyun, Achangwa, Chiara, Hwang, Joo-Hee, Hwang, Jeong-Hwan, and Lee, Chang-Seop
- Subjects
PERFORINS ,SARS-CoV-2 ,GRANZYMES ,CYTOTOXIC T cells - Abstract
Background: As many SARS-CoV-2 infections are asymptomatic, it could be useful to be able to determine how much time has passed since infection. We explored the changes in the temporal levels of T cell-related proteins (including perforin and granzymes) in the sera of patients with SARS-CoV-2 infection using a commercially available assay. Methods: This study enrolled 36 patients infected with SARS-CoV-2 and 20 healthy control participants. Blood samples were collected at three different times based on the number of days since symptom onset (early phase: 1–5 days, mid-phase: 6–10 days, late phase: 11–18 days). We assessed the temporal changes in the serum levels of perforin and granzymes in patients with SARS-CoV-2 infection by comparing the results with those obtained in the healthy control group. Results: We identified a significantly low level of perforin in the early phase of SARS-CoV-2 infection (p < 0.01), which was restored to normal during the mid- and late phases of the infection. However, there was no difference in the temporal change in the level of granzymes in SARS-CoV-2-infected patients compared to the healthy control group. Conclusions: This finding suggests that SARS-CoV-2 infection paralyzed the perforin expression in the early period immediately after infection. Thus, serum perforin is a potential marker for identifying the acute phase of SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
13. MK2 drives progression of pancreas and colon cancers by suppressing CD8+ T cell cytotoxic function and is a potential immunotherapy target.
- Author
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Jacenik, Damian, Lebish, Eric J., and Beswick, Ellen J.
- Subjects
CYTOTOXIC T cells ,PANCREATIC cancer ,MITOGEN-activated protein kinase kinase ,CELL physiology ,COLON cancer - Abstract
Background: Immune cell composition is a critical and dynamic component of the tumor microenvironment, which has an impact on immunosuppression and progression of cancer. T cells, especially CD8
+ T cells, are one of the major immune cell types responsible for tumor cell killing employing receptor-ligand mediated apoptosis and/or releasing lytic granules among others. Accumulating evidence highlighted that adoptive transfer of activated and/or modified immune cells can enhance anti-tumorigenic immune responses and serve as promising therapy approach for patients with cancers. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a serine/threonine protein kinase, which controls production and secretion of numerous pro-inflammatory cytokines and chemokines involved in tumorigenesis. However, limited efforts have been made to learn how MK2 may affects CD8+ T cell action and function in the tumor microenvironment especially in gastrointestinal cancers. Methods: To explore the therapeutic potential of MK2 in the immune response mediated by CD8+ T cells, RAG1 knockout mice with PK5L1940 and BRAF cellsderived allograft tumors were treated with WT or MK2 knockout CD8+ T cells. The phenotype of CD8+ T cells with MK2 depletion were evaluated in vitro. Immunofluorescence staining, real-time PCR and multiplex analysis were utilized to estimate the expression of apoptotic and lytic factors. Results: Here, we show that CD8+ T cells with MK2 depletion prevent gastrointestinal cancer growth, which is accompanied by enhanced expression and secretion of factors related to apoptosis. Moreover, using in vitro and in vivo approaches, we found that depletion of MK2 lead to hyperactivation of CD8+ T cells and enhanced anti-tumor immunity. Conclusion: Overall, we documented that MK2 drives the progression of gastrointestinal cancers and prevents immune response generated by CD8+ T cells suggesting potential implications of MK2 in the immunotherapy of gastrointestinal cancers. [ABSTRACT FROM AUTHOR]- Published
- 2023
- Full Text
- View/download PDF
14. Dendritic cell-mimicking scaffolds for ex vivo T cell expansion
- Author
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Hye Sung Kim, Tzu-Chieh Ho, Moshe J. Willner, Michael W. Becker, Hae-Won Kim, and Kam W. Leong
- Subjects
Adoptive cell therapy ,Ex vivo T cell expansion ,Cytotoxic T cell ,Dendritic cell membrane ,Cell membrane coating ,Scaffold ,Materials of engineering and construction. Mechanics of materials ,TA401-492 ,Biology (General) ,QH301-705.5 - Abstract
We propose an ex vivo T cell expansion system that mimics natural antigen-presenting cells (APCs) for adoptive cell therapy (ACT). Microfiber scaffolds coated with dendritic cell (DC) membrane replicate physicochemical properties of dendritic cells specific for T cell activation such as rapid recognition by T cells, long duration of T cell tethering, and DC-specific co-stimulatory cues. The DC membrane-coated scaffold is first surface-immobilized with T cell stimulatory ligands, anti-CD3 (αCD3) and anti-CD28 (αCD28) antibodies, followed by adsorption of releasable interleukin-2 (IL-2). The scaffolds present both surface and soluble cues to T cells ex vivo in the same way that these cues are presented by natural APCs in vivo. We demonstrate that the DC-mimicking scaffold promotes greater polyclonal expansion of primary human T cells as compared to αCD3/αCD28-functionalized Dynabead. More importantly, major histocompatibility complex molecules derived from the DC membrane of the scaffold allow antigen-specific T cell expansion with target cell-specific killing ability. In addition, most of the expanded T cells (∼97%) can be harvested from the scaffold by density gradient centrifugation. Overall, the DC-mimicking scaffold offers a scalable, modular, and customizable platform for rapid expansion of highly functional T cells for ACT.
- Published
- 2023
- Full Text
- View/download PDF
15. Natural Killer Cells and Cytotoxic T Cells: Complementary Partners against Microorganisms and Cancer
- Author
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Aristo Vojdani, Sadi Koksoy, Elroy Vojdani, Mark Engelman, Carina Benzvi, and Aaron Lerner
- Subjects
NK subpopulation ,natural killer cell ,cytotoxic T cell ,microorganism ,granules ,innate immunity ,Biology (General) ,QH301-705.5 - Abstract
Natural killer (NK) cells and cytotoxic T (CD8+) cells are two of the most important types of immune cells in our body, protecting it from deadly invaders. While the NK cell is part of the innate immune system, the CD8+ cell is one of the major components of adaptive immunity. Still, these two very different types of cells share the most important function of destroying pathogen-infected and tumorous cells by releasing cytotoxic granules that promote proteolytic cleavage of harmful cells, leading to apoptosis. In this review, we look not only at NK and CD8+ T cells but also pay particular attention to their different subpopulations, the immune defenders that include the CD56+CD16dim, CD56dimCD16+, CD57+, and CD57+CD16+ NK cells, the NKT, CD57+CD8+, and KIR+CD8+ T cells, and ILCs. We examine all these cells in relation to their role in the protection of the body against different microorganisms and cancer, with an emphasis on their mechanisms and their clinical importance. Overall, close collaboration between NK cells and CD8+ T cells may play an important role in immune function and disease pathogenesis. The knowledge of how these immune cells interact in defending the body against pathogens and cancers may help us find ways to optimize their defensive and healing capabilities with methods that can be clinically applied.
- Published
- 2024
- Full Text
- View/download PDF
16. Heterogeneity of memory T cells in aging
- Author
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Abhinav Jain, Ines Sturmlechner, Cornelia M. Weyand, and Jörg J. Goronzy
- Subjects
memory T cell ,aging ,cytotoxic T cell ,vaccine ,T cell durability ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Immune memory is a requisite and remarkable property of the immune system and is the biological foundation of the success of vaccinations in reducing morbidity from infectious diseases. Some vaccines and infections induce long-lasting protection, but immunity to other vaccines and particularly in older adults rarely persists over long time periods. Failed induction of an immune response and accelerated waning of immune memory both contribute to the immuno-compromised state of the older population. Here we review how T cell memory is influenced by age. T cell memory is maintained by a dynamic population of T cells that are heterogeneous in their kinetic parameters under homeostatic condition and their function. Durability of T cell memory can be influenced not only by the loss of a clonal progeny, but also by broader changes in the composition of functional states and transition of T cells to a dysfunctional state. Genome-wide single cell studies on total T cells have started to provide insights on the influence of age on cell heterogeneity over time. The most striking findings were a trend to progressive effector differentiation and the activation of pro-inflammatory pathways, including the emergence of CD4+ and CD8+ cytotoxic subsets. Genome-wide data on antigen-specific memory T cells are currently limited but can be expected to provide insights on how changes in T cell subset heterogeneity and transcriptome relate to durability of immune protection.
- Published
- 2023
- Full Text
- View/download PDF
17. Emerging roles of SARS-CoV-2 Spike-ACE2 in immune evasion and pathogenesis.
- Author
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Baldari, Cosima T., Onnis, Anna, Andreano, Emanuele, Del Giudice, Giuseppe, and Rappuoli, Rino
- Subjects
- *
CYTOTOXIC T cells , *SARS-CoV-2 , *CYTOSKELETAL proteins , *COVID-19 , *ANGIOTENSIN converting enzyme , *IMMUNE reconstitution inflammatory syndrome - Abstract
CD8+ cytotoxic T lymphocytes (CTLs) are major targets of SARS-CoV-2. Immunological synapse (IS) formation has emerged as an Achille's heel in COVID-19. Several accessory proteins disrupt antigen presentation by virally infected cells, and spike directly suppresses IS assembly by interacting with angiotensin-converting enzyme 2 receptor (ACE2) on CTLs. While ACE2 was previously considered a component of the renin–angiotensin system, recent reports highlight a role for ACE2 as a signaling receptor that acts independently of its ectoenzyme activity. Accumulating evidence shows a widespread distribution of ACE2 in different tissues and organs which are affected in COVID-19 patients, presumably contributing in part to extrapulmonary disease manifestations. SARS-CoV-2 exploits both the structural and accessory proteins encoded by its genome to systematically subvert the innate and adaptive immune defenses of the host. The recent finding that the SARS-CoV-2 spike protein exploits ACE2 signaling to suppress immunological synapse assembly and CD8+ cytotoxic T lymphocyte-mediated killing highlights a potential role for the spike–ACE2 axis in the extrapulmonary manifestations of COVID-19. The COVID-19 pandemic, caused by SARS-CoV-2, has caused an estimated 5 billion infections and 20 million deaths by respiratory failure. In addition to the respiratory disease, SARS-CoV-2 infection has been associated with many extrapulmonary complications not easily explainable by the respiratory infection. A recent study showed that the SARS-CoV-2 spike protein, which mediates cell entry by binding to the angiotensin-converting enzyme 2 (ACE2) receptor, signals through ACE2 to change host cell behavior. In CD8+ T cells, spike-dependent ACE2-mediated signaling suppresses immunological synapse (IS) formation and impairs their killing ability, leading to immune escape of virus-infected cells. In this opinion article, we discuss the consequences of ACE2 signaling on the immune response and propose that it contributes to the extrapulmonary manifestations of COVID-19. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
18. Inhibitory Effect of Zinc on Colorectal Cancer by Granzyme B Transcriptional Regulation in Cytotoxic T Cells.
- Author
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Nakagawa, Naoya, Fujisawa, Yutaka, Xiang, Huihui, Kitamura, Hidemitsu, and Nishida, Keigo
- Subjects
- *
CYTOTOXIC T cells , *GENETIC transcription regulation , *COLORECTAL cancer , *GRANZYMES , *ZINC , *CELLULAR immunity - Abstract
Zinc is one of the essential trace elements and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, and the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added group than in the normal zinc intake group, and about half as many in the high-zinc-intake group as in the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. In this study, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and increases the transcription of granzyme B, one of the key molecules in tumor immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
19. Immunology: An Overview
- Author
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Maleki, Arash, Drenen, Kayla, Foster, Charles Stephen, Perez, Victor L., Section editor, Foster, C. Stephen, Section editor, Albert, Daniel M., editor, Miller, Joan W., editor, Azar, Dimitri T., editor, and Young, Lucy H., editor
- Published
- 2022
- Full Text
- View/download PDF
20. TB Vaccines: What Type of TB Vaccines Are Studied and Will Be Available in the Future?
- Author
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Okada, Masaji, Kita, Yoko, Nakamura, Hiroyuki, Series Editor, Aoshiba, Kazutetsu, Series Editor, Saito, Takefumi, editor, Narita, Masahiro, editor, and Daley, Charles L., editor
- Published
- 2022
- Full Text
- View/download PDF
21. Add-On Effect of Hemagglutinating Virus of Japan Envelope Combined with Chemotherapy or Immune Checkpoint Inhibitor against Malignant Pleural Mesothelioma: An In Vivo Study.
- Author
-
Sakura, Kazuma, Sasai, Masao, Funaki, Soichiro, Shintani, Yasushi, Okumura, Meinoshin, and Kaneda, Yasufumi
- Subjects
- *
THERAPEUTIC use of antineoplastic agents , *MESOTHELIOMA , *IMMUNE checkpoint inhibitors , *COMBINATION drug therapy , *IN vivo studies , *CANCER chemotherapy , *ANIMAL experimentation , *TREATMENT effectiveness , *PLEURAL tumors , *IMMUNITY , *RESEARCH funding , *PARAMYXOVIRUSES , *MICE - Abstract
Simple Summary: In this study, we report that the combination of existing therapeutic agents and hemagglutinating virus of Japan envelope (HVJ-E), a virus-inactivating agent, may be a more effective treatment agent for pleural mesothelioma, a refractory cancer for which no effective treatment has been established. We have already reported that HVJ-E, which activates antitumor immunity and induces apoptosis in cancer, can provide a different mechanism for effective treatment. In this report, the antitumor effect of HVJ-E in combination with chemotherapy or immune checkpoint inhibitors (ICIs) activated antitumor immunity in a mouse model of malignant pleural mesothelioma-bearing tumor and significantly enhanced antitumor efficacy compared to single-agent therapy. We report that the use of HVJ-E in combination with chemotherapy or ICIs, which are already used in clinical practice, may be more effective than single-agent therapy. However, further clinical studies are needed before the combination therapy can be used in clinical practice. Malignant pleural mesothelioma (MPM) is a refractory tumor because most of the lesions are already disseminated at diagnosis. Previously, the main treatment for MPM was combination chemotherapy. However, recently, immune checkpoint inhibitors (ICIs) are also used. For better efficacy of MPM treatment, we focused on hemagglutinating virus of Japan envelope (HVJ-E), which activates antitumor immunity and induces tumor-specific cell death. In this paper, we aimed to determine whether HVJ-E as a single agent therapy or in combination with chemotherapy or ICIs is effective in MPM bearing mouse. We confirmed its antitumor efficacy in MPM-bearing mouse. HVJ-E significantly prolonged the survival of human MPM-bearing mouse compared to that of control mouse and when combined with CDDP. This efficacy was lost in NOD-SCID mouse, suggesting that activation of innate immunity by HVJ-E was related to the survival rate. HVJ-E also showed antitumor efficacy in murine MPM-bearing mouse. The combination of chemotherapy and HVJ-E caused a significant increase in cytotoxic T cells (CTLs) compared to chemotherapy alone, suggesting that not only innate immunity activated by HVJ-E but also the increase in CTLs contributed to improved survival. The combination of anti-PD-1 antibody and HVJ-E significantly prolonged the survival rate of murine MPM-bearing mouse. Further, HVJ-E might have exhibited antitumor effects by maintaining immunogenicity against tumors. We believe that HVJ-E may be a beneficial therapy to improve MPM treatment in the future. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
22. A Review of Immune Checkpoint Blockade for the General Surgeon.
- Author
-
Baldwin, Xavier L., Spanheimer, Philip M., and Downs-Canner, Stephanie
- Subjects
- *
IMMUNE checkpoint proteins , *T cells , *CYTOTOXIC T cells , *SURGEONS , *IMMUNE system - Abstract
The immune system is a complex and interconnected system that has evolved to protect its host from foreign pathogens. CD8+ T cells are a type of immune cell that can be directly lethal to tumor cells. However, their tumor killing capabilities can be inhibited by checkpoint molecules. During the last decade, the development of medications that block these checkpoint molecules has revolutionized treatment for some cancer types and indications for use continue to grow. As usage of immunotherapy increases, toxicities and adverse events unique to immunotherapy are becoming more prevalent. Here, we review the commonly targeted inhibitory molecules along with their food and drug administration-approved indications in various cancer therapeutic regimens, immunotherapy-related toxicities, and how this may impact surgical planning. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
23. MK2 drives progression of pancreas and colon cancers by suppressing CD8+ T cell cytotoxic function and is a potential immunotherapy target
- Author
-
Damian Jacenik, Eric J. Lebish, and Ellen J. Beswick
- Subjects
mitogen-activated protein kinase-activated protein kinase 2 ,MAPKAPK2 ,MK2 ,cytotoxic T cell ,CD8+ T cell ,pancreas cancer ,Immunologic diseases. Allergy ,RC581-607 - Abstract
BackgroundImmune cell composition is a critical and dynamic component of the tumor microenvironment, which has an impact on immunosuppression and progression of cancer. T cells, especially CD8+ T cells, are one of the major immune cell types responsible for tumor cell killing employing receptor-ligand mediated apoptosis and/or releasing lytic granules among others. Accumulating evidence highlighted that adoptive transfer of activated and/or modified immune cells can enhance anti-tumorigenic immune responses and serve as promising therapy approach for patients with cancers. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a serine/threonine protein kinase, which controls production and secretion of numerous pro-inflammatory cytokines and chemokines involved in tumorigenesis. However, limited efforts have been made to learn how MK2 may affects CD8+ T cell action and function in the tumor microenvironment especially in gastrointestinal cancers.MethodsTo explore the therapeutic potential of MK2 in the immune response mediated by CD8+ T cells, RAG1 knockout mice with PK5L1940 and BRAF cells-derived allograft tumors were treated with WT or MK2 knockout CD8+ T cells. The phenotype of CD8+ T cells with MK2 depletion were evaluated in vitro. Immunofluorescence staining, real-time PCR and multiplex analysis were utilized to estimate the expression of apoptotic and lytic factors.ResultsHere, we show that CD8+ T cells with MK2 depletion prevent gastrointestinal cancer growth, which is accompanied by enhanced expression and secretion of factors related to apoptosis. Moreover, using in vitro and in vivo approaches, we found that depletion of MK2 lead to hyperactivation of CD8+ T cells and enhanced anti-tumor immunity.ConclusionOverall, we documented that MK2 drives the progression of gastrointestinal cancers and prevents immune response generated by CD8+ T cells suggesting potential implications of MK2 in the immunotherapy of gastrointestinal cancers.
- Published
- 2023
- Full Text
- View/download PDF
24. MicroRNA regulation of CD8+ T cell responses.
- Author
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Gagnon, John D and Ansel, K Mark
- Subjects
MicroRNA ,T cell exhaustion ,T cell memory ,cytotoxic T cell ,Cancer ,Biotechnology ,Genetics ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning - Abstract
MicroRNAs (miRNAs) are a class of short noncoding RNAs that play critical roles in the regulation of a broad range of biological processes. Like transcription factors, miRNAs exert their effects by modulating the expression of networks of genes that operate in common or convergent pathways. CD8+ T cells are critical agents of the adaptive immune system that provide protection from infection and cancer. Here, we review the important roles of miRNAs in the regulation of CD8+ T cell biology and provide perspectives on the broader emerging principles of miRNA function.
- Published
- 2019
25. MicroRNA regulation of CD8 + T cell responses
- Author
-
Gagnon, John D and Ansel, K Mark
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Cancer ,Genetics ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Underpinning research ,MicroRNA ,T cell exhaustion ,T cell memory ,cytotoxic T cell - Abstract
MicroRNAs (miRNAs) are a class of short noncoding RNAs that play critical roles in the regulation of a broad range of biological processes. Like transcription factors, miRNAs exert their effects by modulating the expression of networks of genes that operate in common or convergent pathways. CD8+ T cells are critical agents of the adaptive immune system that provide protection from infection and cancer. Here, we review the important roles of miRNAs in the regulation of CD8+ T cell biology and provide perspectives on the broader emerging principles of miRNA function.
- Published
- 2019
26. Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma
- Author
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Muthulekha Swamydas, Elena V. Murphy, James J. Ignatz-Hoover, Ehsan Malek, and James J. Driscoll
- Subjects
Multiple myeloma ,Immunotherapy ,Immune escape ,Drug resistance ,Proteasome ,Cytotoxic T cell ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Multiple myeloma is an incurable cancer characterized by the uncontrolled growth of malignant plasma cells nurtured within a permissive bone marrow microenvironment. While patients mount numerous adaptive immune responses directed against their disease, emerging data demonstrate that tumor intrinsic and extrinsic mechanisms allow myeloma cells to subvert host immunosurveillance and resist current therapeutic strategies. Myeloma downregulates antigens recognized by cellular immunity and modulates the bone marrow microenvironment to promote uncontrolled tumor proliferation, apoptotic resistance, and further hamper anti-tumor immunity. Additional resistance often develops after an initial clinical response to small molecules, immune-targeting antibodies, immune checkpoint blockade or cellular immunotherapy. Profound quantitative and qualitative dysfunction of numerous immune effector cell types that confer anti-myeloma immunity further supports myelomagenesis, disease progression and the emergence of drug resistance. Identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of rationally-designed drug combinations that prevent or overcome drug resistance to improve patient survival. Here, we summarize various mechanisms of immune escape as a means to inform novel strategies that may restore and improve host anti-myeloma immunity.
- Published
- 2022
- Full Text
- View/download PDF
27. Temporal Dynamics of Serum Perforin and Granzyme during the Acute Phase of SARS-CoV-2 Infection
- Author
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MD Tazikur Rahman, Sukhyun Ryu, Chiara Achangwa, Joo-Hee Hwang, Jeong-Hwan Hwang, and Chang-Seop Lee
- Subjects
perforin ,granzyme ,SARS-CoV-2 ,cytotoxic T cell ,Medicine - Abstract
Background: As many SARS-CoV-2 infections are asymptomatic, it could be useful to be able to determine how much time has passed since infection. We explored the changes in the temporal levels of T cell-related proteins (including perforin and granzymes) in the sera of patients with SARS-CoV-2 infection using a commercially available assay. Methods: This study enrolled 36 patients infected with SARS-CoV-2 and 20 healthy control participants. Blood samples were collected at three different times based on the number of days since symptom onset (early phase: 1–5 days, mid-phase: 6–10 days, late phase: 11–18 days). We assessed the temporal changes in the serum levels of perforin and granzymes in patients with SARS-CoV-2 infection by comparing the results with those obtained in the healthy control group. Results: We identified a significantly low level of perforin in the early phase of SARS-CoV-2 infection (p < 0.01), which was restored to normal during the mid- and late phases of the infection. However, there was no difference in the temporal change in the level of granzymes in SARS-CoV-2-infected patients compared to the healthy control group. Conclusions: This finding suggests that SARS-CoV-2 infection paralyzed the perforin expression in the early period immediately after infection. Thus, serum perforin is a potential marker for identifying the acute phase of SARS-CoV-2 infection.
- Published
- 2023
- Full Text
- View/download PDF
28. From protein-protein interactions to immune modulation: Therapeutic prospects of targeting Neuropilin-1 in high-grade glioma.
- Author
-
Smith, Gregory T., Radin, Daniel P., and Tsirka, Stella E.
- Subjects
IMMUNOREGULATION ,REGULATORY T cells ,PROTEIN-protein interactions ,CYTOTOXIC T cells ,PATHOLOGICAL physiology ,BRAIN tumors - Abstract
In the past several years there has been a marked increase in our understanding of the pathophysiological hallmarks of glioblastoma development and progression, with specific respect to the contribution of the glioma tumor microenvironment to the rapid progression and treatment resistance of high-grade gliomas. Despite these strides, standard of care therapy still only targets rapidly dividing tumor cells in the glioma, and does little to curb the pro-tumorigenic functions of non-cancerous cells entrenched in the glioma microenvironment. This tumor promoting environment as well as the heterogeneity of high-grade gliomas contribute to the poor prognosis of this malignancy. The interaction of non-malignant cells in the microenvironment with the tumor cells accentuate phenotypes such as rapid proliferation or immunosuppression, so therapeutically modulating one target expressed on one cell type may be insufficient to restrain these rapidly developing neoplasias. With this in mind, identifying a target expressed on multiple cell types and understanding how it governs tumor-promoting functions in each cell type may have great utility in better managing this disease. Herein, we review the physiology and pathological effects of Neuropilin-1, a transmembrane co-receptor which mediates signal transduction pathways when associated with multiple other receptors. We discuss its effects on the properties of endothelial cells and on immune cell types within gliomas including glioma-associated macrophages, microglia, cytotoxic T cells and T regulatory cells. We also consider its effects when elaborated on the surface of tumor cells with respect to proliferation, stemness and treatment resistance, and review attempts to target Neuroplin-1 in the clinical setting. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
29. A role for an HTLV-1 vaccine?
- Author
-
Ratner, Lee
- Subjects
TECHNOLOGICAL innovations ,CYTOTOXIC T cells ,SEXUAL intercourse ,VACCINES ,SEARCH warrants (Law) - Abstract
HTLV-1 is a global infection with 5-20 million infected individuals. Although only a minority of infected individuals develop myelopathy, lymphoproliferative malignancy, or inflammatory disorders, infection is associated with immunosuppression and shorter survival. Transmission of HTLV-1 is through contaminated blood or needles, mother-to-child exposure through breastfeeding, and sexual intercourse. HTLV-1 is a delta retrovirus that expresses immunogenic Gag, Envelope, TAX, and Hbz proteins. Neutralizing antibodies have been identified directed against the surface envelope protein, and cytotoxic T-cell epitopes within TAX have been characterized. Thus far, there have been few investigations of vaccines directed against each of these proteins, with limited responses, thus far. However, with new technologies developed in the last few years, a renewed investigation is warranted in search for a safe and effective HTLV-1 vaccine. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
30. Growth arrest‐specific transcript 5 represses endometrial cancer development by promoting antitumor function of tumor‐associated macrophages.
- Author
-
Tu, Jiajie, Tan, Xuewen, Chen, Yu, Li, Zhe, Zhang, Yuanyuan, Chen, Xiaochun, Yang, Huan, Chen, He, and Yu, Zhiying
- Abstract
The tumor‐suppressor role of long noncoding RNA (lncRNA) growth arrest‐specific transcript 5 (GAS5) has been proven in various types of cancer. However, the specific function of GAS5 in tumor‐associated macrophages (TAMs) of endometrial cancer (EC) is elusive. Quantitative PCR results showed that GAS5 expression decreased in EC tissues and primary TAMs from EC tumors. Tumor‐associated macrophage infiltration was significantly positively associated with the developmental stage of EC. Direct coculture of GAS5‐overexpressing TAMs and EC cells showed that GAS5 enhanced phagocytosis, antigen presentation, and activation of cytotoxic T cells, and repressed "Don't eat me" signals between TAMs and EC cells. Tumor formation in immunodeficient mice showed that GAS5‐overexpressing macrophages could repress EC formation in vivo. GAS5 promoted M1 polarization by activating the microRNA‐21– phosphatase and tensin homolog (PTEN)–AKT signaling pathway and directly repressing the nuclear accumulation and phosphorylation of oncogenic yes‐associated protein 1 (YAP1) in TAMs. GAS5 inhibited the development of EC from both innate and adaptive immunity by transforming TAMs from a protumor to an antitumor phenotype. These antitumor effects of GAS5 on TAMs were mediated by the activation of the miR‐21‐PTEN‐AKT pathway and inhibition of YAP1. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
31. When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4+ T Cells.
- Author
-
Hoeks, Cindy, Duran, Gayel, Hellings, Niels, and Broux, Bieke
- Subjects
CYTOTOXIC T cells ,CD4 lymphocyte count ,PERIPHERAL circulation ,T cells ,CELL analysis - Abstract
Once regarded as an experimental artefact, cytotoxic CD4+ T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naïve CD4+ T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
32. Remodeling the hepatic immune microenvironment and demolishing T cell traps to enhance immunotherapy efficacy in liver metastasis.
- Author
-
Luo Z, Jiang M, Cheng N, Zhao X, Liu H, Wang S, Lin Q, Huang J, Guo X, Liu X, Shan X, Lu Y, Shi Y, Luo L, and You J
- Abstract
Immune checkpoint inhibitors (ICIs) exhibit compromised therapeutic efficacy in many patients with advanced cancers, particularly those with liver metastases. Much of this incapability can be ascribed as an irresponsiveness resulting from the "cold" hepatic tumor microenvironment that acts as T cell "traps" for which there currently lack countermeasures. We report a novel nanomedicine that converts the hepatic immune microenvironment to a "hot" phenotype by targeting hepatic macrophage-centric T cell elimination. Using the nanomedicine, composed of KIRA6 (an endothelium reticulum stress inhibitor), α-Tocopherol nanoemulsions, and anti-PD1 antibodies, we found its potency in murine models of orthotopic colorectal tumors and hepatic metastases, restoring immune responses and enhancing anti-tumor effects. A post-treatment scrutiny of the immune microenvironment landscape in the liver reveals repolarization of immunosuppressive hepatic macrophages, upregulation of Th1-like effector CD4
+ T cells, and rejuvenation of dendritic cells along with CD8+ T cells. These findings suggest adaptations of liver-centric immune milieu modulation strategies to improve the efficacy of ICIs for a variety of "cold" tumors and their liver metastases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
- Full Text
- View/download PDF
33. Next Generation of Cancer Immunotherapy: Targeting the Cancer-Immunity Cycle with Nanotechnology
- Author
-
Ma, Yifan, Cai, Lintao, Xu, Haiyan, editor, and Gu, Ning, editor
- Published
- 2020
- Full Text
- View/download PDF
34. From protein-protein interactions to immune modulation: Therapeutic prospects of targeting Neuropilin-1 in high-grade glioma
- Author
-
Gregory T. Smith, Daniel P. Radin, and Stella E. Tsirka
- Subjects
Neuropilin-1 (NRP1) ,high grade glioma (HGG) ,glioma-associated macrophages and microglia ,hypoxia ,angiogenesis ,cytotoxic T cell ,Immunologic diseases. Allergy ,RC581-607 - Abstract
In the past several years there has been a marked increase in our understanding of the pathophysiological hallmarks of glioblastoma development and progression, with specific respect to the contribution of the glioma tumor microenvironment to the rapid progression and treatment resistance of high-grade gliomas. Despite these strides, standard of care therapy still only targets rapidly dividing tumor cells in the glioma, and does little to curb the pro-tumorigenic functions of non-cancerous cells entrenched in the glioma microenvironment. This tumor promoting environment as well as the heterogeneity of high-grade gliomas contribute to the poor prognosis of this malignancy. The interaction of non-malignant cells in the microenvironment with the tumor cells accentuate phenotypes such as rapid proliferation or immunosuppression, so therapeutically modulating one target expressed on one cell type may be insufficient to restrain these rapidly developing neoplasias. With this in mind, identifying a target expressed on multiple cell types and understanding how it governs tumor-promoting functions in each cell type may have great utility in better managing this disease. Herein, we review the physiology and pathological effects of Neuropilin-1, a transmembrane co-receptor which mediates signal transduction pathways when associated with multiple other receptors. We discuss its effects on the properties of endothelial cells and on immune cell types within gliomas including glioma-associated macrophages, microglia, cytotoxic T cells and T regulatory cells. We also consider its effects when elaborated on the surface of tumor cells with respect to proliferation, stemness and treatment resistance, and review attempts to target Neuroplin-1 in the clinical setting.
- Published
- 2022
- Full Text
- View/download PDF
35. When Helpers Go Above and Beyond: Development and Characterization of Cytotoxic CD4+ T Cells
- Author
-
Cindy Hoeks, Gayel Duran, Niels Hellings, and Bieke Broux
- Subjects
CD4 CTL ,cytotoxic T cell ,Th differentiation ,migration ,CD4 cytotoxic cells ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Once regarded as an experimental artefact, cytotoxic CD4+ T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naïve CD4+ T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies.
- Published
- 2022
- Full Text
- View/download PDF
36. Inhibitory Effect of Zinc on Colorectal Cancer by Granzyme B Transcriptional Regulation in Cytotoxic T Cells
- Author
-
Naoya Nakagawa, Yutaka Fujisawa, Huihui Xiang, Hidemitsu Kitamura, and Keigo Nishida
- Subjects
zinc ,cytotoxic T cell ,colorectal cancer ,granzyme B ,tumor immunity ,calcineurin ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Zinc is one of the essential trace elements and is involved in various functions in the body. Zinc deficiency is known to cause immune abnormalities, but the mechanism is not fully understood. Therefore, we focused our research on tumor immunity to elucidate the effect of zinc on colorectal cancer and its mechanisms. Mice were treated with azoxymethane (AOM) and dextran sodium sulfate (DSS) to develop colorectal cancer, and the relationship between zinc content in the diet and the number and area of tumors in the colon was observed. The number of tumors in the colon was significantly higher in the no-zinc-added group than in the normal zinc intake group, and about half as many in the high-zinc-intake group as in the normal-zinc-intake group. In T-cell-deficient mice, the number of tumors in the high-zinc-intake group was similar to that in the normal-zinc-intake group, suggesting that the inhibitory effect of zinc was dependent on T cells. Furthermore, we found that the amount of granzyme B transcript released by cytotoxic T cells upon antigen stimulation was significantly increased by the addition of zinc. We also showed that granzyme B transcriptional activation by zinc addition was dependent on calcineurin activity. In this study, we have shown that zinc exerts its tumor-suppressive effect by acting on cytotoxic T cells, the center of cellular immunity, and increases the transcription of granzyme B, one of the key molecules in tumor immunity.
- Published
- 2023
- Full Text
- View/download PDF
37. The presence of serum anti‐SARS‐CoV‐2 IgA appears to protect primary health care workers from COVID‐19.
- Author
-
Hennings, Viktoria, Thörn, Karolina, Albinsson, Sofie, Lingblom, Christine, Andersson, Kerstin, Andersson, Christer, Järbur, Katarina, Pullerits, Rille, Idorn, Manja, Paludan, Søren R., Eriksson, Kristina, and Wennerås, Christine
- Subjects
MEDICAL personnel ,COMMUNITY health workers ,PRIMARY health care ,IMMUNOGLOBULIN A ,COVID-19 pandemic ,CLINICAL trials monitoring - Abstract
The patterns of humoral and cellular responses to SARS‐CoV‐2 were studied in Swedish primary health care workers (n = 156) for 6 months during the Covid‐19 pandemic. Serum IgA and IgG to SARS‐CoV‐2, T‐cell proliferation and cytokine secretion, demographic and clinical data, PCR‐verified infection, and self‐reported symptoms were monitored. The multivariate method OPLS‐DA was used to identify immune response patterns coupled to protection from Covid‐19. Contracting Covid‐19 was associated with SARS‐CoV‐2‐specific neutralizing serum IgG, T cell, IFN‐γ, and granzyme B responses to SARS‐CoV‐2, self‐reported typical Covid‐19 symptoms, male sex, higher BMI, and hypertension. Not contracting Covid‐19 was associated with female sex, IgA‐dominated, or no antibody responses to SARS‐CoV‐2, airborne allergy, and smoking. The IgG‐responders had SARS‐CoV‐2‐specific T‐cell responses including a cytotoxic CD4+ T‐cell population expressing CD25, CD38, CD69, CD194, CD279, CTLA‐4, and granzyme B. IgA‐responders with no IgG response to SARS‐CoV‐2 constituted 10% of the study population. The IgA responses were partially neutralizing and only seen in individuals who did not succumb to Covid‐19. To conclude, serum IgG‐dominated responses correlated with T‐cell responses to SARS‐CoV‐2 and PCR‐confirmed Covid‐19, whereas IgA‐dominated responses correlated with not contracting the infection. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
38. The Expanding Arsenal of Cytotoxic T Cells.
- Author
-
Cassioli, Chiara and Baldari, Cosima T.
- Subjects
CYTOTOXIC T cells ,T cell receptors ,ANTIGEN receptors ,IMMUNE recognition ,DEATH receptors - Abstract
Cytotoxic T cells (CTLs) are the main cellular mediators of the adaptive immune defenses against intracellular pathogens and malignant cells. Upon recognition of specific antigen on their cellular target, CTLs assemble an immunological synapse where they mobilise their killing machinery that is released into the synaptic cleft to orchestrate the demise of their cell target. The arsenal of CTLs is stored in lysosome-like organelles that undergo exocytosis in response to signals triggered by the T cell antigen receptor following antigen recognition. These organelles include lytic granules carrying a cargo of cytotoxic proteins packed on a proteoglycan scaffold, multivesicular bodies carrying the death receptor ligand FasL, and the recently discovered supramolecular attack particles that carry a core of cytotoxic proteins encased in a non-membranous glycoprotein shell. Here we will briefly review the main features of these killing entities and discuss their interrelationship and interplay in CTL-mediated killing. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
39. Ketone Bodies Improve Human CD8+ Cytotoxic T-Cell Immune Response During COVID-19 Infection
- Author
-
Simon Hirschberger, Luca Gellert, David Effinger, Maximilian Muenchhoff, Markus Herrmann, Josef-Maria Briegel, Bernhard Zwißler, and Simone Kreth
- Subjects
Ketogenic Diet (KD) ,SARS-CoV-2 ,COVID-19 ,T-cell immunometabolism ,cytotoxic T cell ,metabolic therapy ,Medicine (General) ,R5-920 - Abstract
Severe COVID-19 is characterized by profound CD8+ T-cell dysfunction, which cannot be specifically treated to date. We here investigate whether metabolic CD8+ T-cell reprogramming by ketone bodies could be a promising strategy to overcome the immunoparalysis in COVID-19 patients. This approach was triggered by our recent pioneering study, which has provided evidence that CD8+ T-cell capacity in healthy subjects could be significantly empowered by a Ketogenic Diet. These improvements were achieved by immunometabolic rewiring toward oxidative phosphorylation. We here report similar strengthening of CD8+ T cells obtained from severely diseased COVID-19 patients: Flow cytometry and ELISA revealed elevated cytokine expression and secretion (up to + 24%) upon ketone treatment and enhanced cell lysis capacity (+ 21%). Metabolic analyses using Seahorse technology revealed upregulated mitochondrial respiratory chain activity (+ 25%), enabling both superior energy supply (+ 44%) and higher mitochondrial reactive oxygen species signaling. These beneficial effects of ketones might represent evolutionary conserved mechanisms to strengthen human immunity. Our findings pave the road for metabolic treatment studies in COVID-19.
- Published
- 2022
- Full Text
- View/download PDF
40. The Expanding Arsenal of Cytotoxic T Cells
- Author
-
Chiara Cassioli and Cosima T. Baldari
- Subjects
lytic granule ,SMAP ,FasL ,cytotoxic T cell ,granzyme ,perforin ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Cytotoxic T cells (CTLs) are the main cellular mediators of the adaptive immune defenses against intracellular pathogens and malignant cells. Upon recognition of specific antigen on their cellular target, CTLs assemble an immunological synapse where they mobilise their killing machinery that is released into the synaptic cleft to orchestrate the demise of their cell target. The arsenal of CTLs is stored in lysosome-like organelles that undergo exocytosis in response to signals triggered by the T cell antigen receptor following antigen recognition. These organelles include lytic granules carrying a cargo of cytotoxic proteins packed on a proteoglycan scaffold, multivesicular bodies carrying the death receptor ligand FasL, and the recently discovered supramolecular attack particles that carry a core of cytotoxic proteins encased in a non-membranous glycoprotein shell. Here we will briefly review the main features of these killing entities and discuss their interrelationship and interplay in CTL-mediated killing.
- Published
- 2022
- Full Text
- View/download PDF
41. Tumor microenvironment and immune response: A gateway to novel therapies in gastrointestinal cancers.
- Author
-
Jacenik, Damian
- Subjects
- *
GASTROINTESTINAL cancer , *MITOGEN-activated protein kinase kinase , *TUMOR microenvironment , *IMMUNE response , *CYTOTOXIC T cells - Abstract
• Gastrointestinal cancers are characterized by alterations in immune response. • Adoptive immune cell therapy may effectively reprogram the gastrointestinal tumor microenvironment. • Th2 cell-mediated immune response inhibits progression of the gastrointestinal cancers. • Immune response against cancer may be improved by targeting mitogen-activated protein kinase-activated protein kinase 2. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
42. A Gene Panel for Early Identification of Future Responders to Immune Checkpoint Blockade.
- Author
-
Panda, Anshuman, Betigeri, Anil, and Ganesan, Shridar
- Subjects
IMMUNE checkpoint proteins ,CYTOTOXIC T lymphocyte-associated molecule-4 ,CYTOTOXIC T cells ,RECEIVER operating characteristic curves ,PROGRAMMED cell death 1 receptors - Abstract
Immune checkpoint blockade (ICB), therapies that target the PD-1 pathway, CTLA-4 pathway, and other checkpoint pathways, lead to durable responses in many cancer types. Since only a minority of patients respond to ICB, it may be useful to identify the future responders early in the course of treatment. In this study we evaluated a small (15 genes) biologically motivated panel, consisting of genes involved in immune activation and checkpoint pathways, for early identification of future responders to ICB. The panel passed consistency check, pathological and in-silico validations, and was an excellent predictor (area under ROC curve >0.95) of eventual response to ICB, both CTLA-4 and PD-1 blockade, when applied to metastatic melanoma patients undergoing ICB (i.e., "on-treatment") in a publicly available dataset. These results suggest that this small biologically motivated panel may be useful for early identification of future responders to ICB. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
43. Cancer immunotherapy using artificial adjuvant vector cells to deliver NY‐ESO‐1 antigen to dendritic cells in situ.
- Author
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Fujii, Shin‐ichiro, Yamasaki, Satoru, Hanada, Kenichi, Ueda, Shogo, Kawamura, Masami, and Shimizu, Kanako
- Abstract
NY‐ESO‐1 is a cancer/testis antigen expressed in various cancer types. However, the induction of NY‐ESO‐1‐specific CTLs through vaccines is somewhat difficult. Thus, we developed a new type of artificial adjuvant vector cell (aAVC‐NY‐ESO‐1) expressing a CD1d‐NKT cell ligand complex and a tumor‐associated antigen, NY‐ESO‐1. First, we determined the activation of invariant natural killer T (iNKT) and natural killer (NK) cell responses by aAVC‐NY‐ESO‐1. We then showed that the NY‐ESO‐1‐specific CTL response was successfully elicited through aAVC‐NY‐ESO‐1 therapy. After injection of aAVC‐NY‐ESO‐1, we found that dendritic cells (DCs) in situ expressed high levels of costimulatory molecules and produced interleukn‐12 (IL‐12), indicating that DCs undergo maturation in vivo. Furthermore, the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was delivered to the DCs in vivo, and it was presented on MHC class I molecules. The cross‐presentation of the NY‐ESO‐1 antigen was absent in conventional DC‐deficient mice, suggesting a host DC‐mediated CTL response. Thus, this strategy helps generate sufficient CD8+ NY‐ESO‐1‐specific CTLs along with iNKT and NK cell activation, resulting in a strong antitumor effect. Furthermore, we established a human DC‐transferred NOD/Shi‐scid/IL‐2γcnull immunodeficient mouse model and showed that the NY‐ESO‐1 antigen from aAVC‐NY‐ESO‐1 was cross‐presented to antigen‐specific CTLs through human DCs. Taken together, these data suggest that aAVC‐NY‐ESO‐1 has potential for harnessing innate and adaptive immunity against NY‐ESO‐1‐expressing malignancies. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
44. Deciphering mechanisms of immune escape to inform immunotherapeutic strategies in multiple myeloma.
- Author
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Swamydas, Muthulekha, Murphy, Elena V., Ignatz-Hoover, James J., Malek, Ehsan, and Driscoll, James J.
- Subjects
- *
MULTIPLE myeloma , *PLASMA cell diseases , *CELLULAR immunity , *BONE marrow , *CANCER cells , *SMALL molecules - Abstract
Multiple myeloma is an incurable cancer characterized by the uncontrolled growth of malignant plasma cells nurtured within a permissive bone marrow microenvironment. While patients mount numerous adaptive immune responses directed against their disease, emerging data demonstrate that tumor intrinsic and extrinsic mechanisms allow myeloma cells to subvert host immunosurveillance and resist current therapeutic strategies. Myeloma downregulates antigens recognized by cellular immunity and modulates the bone marrow microenvironment to promote uncontrolled tumor proliferation, apoptotic resistance, and further hamper anti-tumor immunity. Additional resistance often develops after an initial clinical response to small molecules, immune-targeting antibodies, immune checkpoint blockade or cellular immunotherapy. Profound quantitative and qualitative dysfunction of numerous immune effector cell types that confer anti-myeloma immunity further supports myelomagenesis, disease progression and the emergence of drug resistance. Identification of tumor intrinsic and extrinsic resistance mechanisms may direct the design of rationally-designed drug combinations that prevent or overcome drug resistance to improve patient survival. Here, we summarize various mechanisms of immune escape as a means to inform novel strategies that may restore and improve host anti-myeloma immunity. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
45. Transcriptional Control of Cell Fate Determination in Antigen-Experienced CD8 T Cells
- Author
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Matthew E. Pipkin and Shanel Tsuda
- Subjects
Effector ,Cell Differentiation ,Biology ,Cell fate determination ,CD8-Positive T-Lymphocytes ,General Biochemistry, Genetics and Molecular Biology ,Chromatin ,Cell biology ,Antigen ,Gene Expression Regulation ,Immunity ,Gene expression ,Transcriptional regulation ,Cytotoxic T cell ,Immunologic Memory - Abstract
Robust immunity to intracellular infections is mediated by antigen-specific naive CD8 T cells that become activated and differentiate into phenotypically and functionally diverse subsets of effector cells, some of which terminally differentiate and others that give rise to memory cells that provide long-lived protection. This developmental system is an outstanding model with which to elucidate how regulation of chromatin structure and transcriptional control establish gene expression programs that govern cell fate determination, insights from which are likely to be useful for informing the design of immunotherapeutic approaches to engineer durable immunity to infections and tumors. A unifying framework that describes how naive CD8 T cells develop into memory cells is still outstanding. We propose a model that incorporates a common early linear path followed by divergent paths that slowly lose capacity to interconvert and discuss classical and contemporary observations that support these notions, focusing on insights from transcriptional control and chromatin regulation.
- Published
- 2024
46. Immunotherapy for Infectious Diseases, Cancer, and Autoimmunity
- Author
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Krause, Peter J., Kavathas, Paula B., Ruddle, Nancy H., Krause, Peter J., editor, Kavathas, Paula B., editor, and Ruddle, Nancy H., editor
- Published
- 2019
- Full Text
- View/download PDF
47. History of Hemophagocytic Lymphohistiocytosis
- Author
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Janka, Gritta E., Cron, Randy Q., editor, and Behrens, Edward M., editor
- Published
- 2019
- Full Text
- View/download PDF
48. A Gene Panel for Early Identification of Future Responders to Immune Checkpoint Blockade
- Author
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Anshuman Panda, Anil Betigeri, and Shridar Ganesan
- Subjects
immune checkpoint inhibitors ,PD-1 blockade ,CTLA-4 blockade ,anti PD1/PDL1 immunotherapy ,interferon gamma (IFNγ) ,cytotoxic T cell ,Genetics ,QH426-470 - Abstract
Immune checkpoint blockade (ICB), therapies that target the PD-1 pathway, CTLA-4 pathway, and other checkpoint pathways, lead to durable responses in many cancer types. Since only a minority of patients respond to ICB, it may be useful to identify the future responders early in the course of treatment. In this study we evaluated a small (15 genes) biologically motivated panel, consisting of genes involved in immune activation and checkpoint pathways, for early identification of future responders to ICB. The panel passed consistency check, pathological and in-silico validations, and was an excellent predictor (area under ROC curve >0.95) of eventual response to ICB, both CTLA-4 and PD-1 blockade, when applied to metastatic melanoma patients undergoing ICB (i.e., “on-treatment”) in a publicly available dataset. These results suggest that this small biologically motivated panel may be useful for early identification of future responders to ICB.
- Published
- 2022
- Full Text
- View/download PDF
49. Aberrant hyperactivation of cytotoxic T-cell as a potential determinant of COVID-19 severity
- Author
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Chang Kyung Kang, Gi-Chan Han, Minji Kim, Gwanghun Kim, Hyun Mu Shin, Kyoung-Ho Song, Pyoeng Gyun Choe, Wan Beom Park, Eu Suk Kim, Hong Bin Kim, Nam-Joong Kim, Hang-Rae Kim, and Myoung-don Oh
- Subjects
COVID-19 ,Severity ,Contraction ,Cytotoxic T cell ,Perforin ,Granzyme B ,Infectious and parasitic diseases ,RC109-216 - Abstract
Objectives: We hypothesized that immune response may contribute to progression of coronavirus disease-19 (COVID-19) at the second week of illness. Therefore, we compared cell-mediated immune (CMI) responses between severe and mild COVID-19 cases. Methods: We examined peripheral blood mononuclear cells of laboratory-confirmed COVID-19 patients from their first and third weeks of illness. Severe pneumonia was defined as an oxygen saturation ≤93% at room air. Expressions of molecules related to T-cell activation and functions were analyzed by flow cytometry. Results: The population dynamics of T cells at the first week were not different between the two groups. However, total numbers of CD4+ and CD8+ T cells tended to be lower in the severe group at the third week of illness. Expressions of Ki-67, PD-1, perforin, and granzyme B in CD4+ or CD8+ T cells were significantly higher in the severe group than in the mild group at the third week. In contrast to the mild group, the levels of their expression did not decrease in the severe group. Conclusions: Severe COVID-19 had a higher degree of proliferation, activation, and cytotoxicity of T-cells at the late phase of illness without cytotoxic T-cell contraction, which might contribute to the development of severe COVID-19.
- Published
- 2020
- Full Text
- View/download PDF
50. Roles of cytotoxic lymphocytes and MIC/LILR families in pathophysiology of Takayasu arteritis
- Author
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Hajime Yoshifuji and Chikashi Terao
- Subjects
Vasculitis ,Genome-wide association study ,Natural killer cell ,Cytotoxic T cell ,Interleukin-6 ,Interleukin-12 ,Pathology ,RB1-214 - Abstract
Abstract Takayasu arteritis (TAK) affects the aorta and its primary branches, mainly in young women. In its advanced stages, it can cause severe complications, such as cerebral infarction, impaired vision, and valvular heart diseases. In the aortic tissue of TAK, there is increased infiltration of cytotoxic lymphocytes, such as natural killer (NK) cells and CD8+T cells, and enhanced expression of accessory molecules, such as major histocompatibility complex (MHC) and MHC class I chain-related gene (MIC) family. Genome-wide association studies on TAK have identified susceptibility genes, such as IL-12p40, MICA, MICB, leukocyte immunoglobulin-like receptor A3 (LILRA3), and LILRB3. Other studies have also shown their involvement in the pathophysiology of TAK. In addition, we reported the importance of NK cells by enhancer enrichment analysis. These results suggest that the gene polymorphisms that potentially upregulate the expression of cytokines and accessory molecules, which contribute to the activation of cytotoxic lymphocytes, are associated with the development of TAK. Based on these results, new molecular targeted therapies look promising.
- Published
- 2020
- Full Text
- View/download PDF
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