16 results
Search Results
2. Characterization of a CXCR4 antagonist TIQ-15 with dual tropic HIV entry inhibition properties.
- Author
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Zhou, Zheng, Guo, Jia, Hetrick, Brian, Tiwari, Sameer, Haikerwal, Amrita, Han, Yang, Bond, Vincent C., Huang, Ming B., Mankowski, Marie K., Snyder, Beth A., Hogan, Priscilla A., Sharma, Savita K., Liotta, Dennis C., Reid, Terry-Elinor, Wilson, Lawrence J., and Wu, Yuntao
- Subjects
CXCR4 receptors ,HIV infections ,CD4 antigen ,CHEMOKINE receptors ,VIRUS diseases - Abstract
The chemokine co-receptors CXCR4 and CCR5 mediate HIV entry and signal transduction necessary for viral infection. However, to date only the CCR5 antagonist maraviroc is approved for treating HIV-1 infection. Given that approximately 50% of late-stage HIV patients also develop CXCR4-tropic virus, clinical anti-HIV CXCR4 antagonists are needed. Here, we describe a novel allosteric CXCR4 antagonist TIQ-15 which inhibits CXCR4-tropic HIV-1 infection of primary and transformed CD4 T cells. TIQ-15 blocks HIV entry with an IC
50 of 13 nM. TIQ-15 also inhibits SDF-1α/CXCR4-mediated cAMP production, cofilin activation, and chemotactic signaling. In addition, TIQ-15 induces CXCR4 receptor internalization without affecting the levels of the CD4 receptor, suggesting that TIQ-15 may act through a novel allosteric site on CXCR4 for blocking HIV entry. Furthermore, TIQ-15 did not inhibit VSV-G pseudotyped HIV-1 infection, demonstrating its specificity in blocking CXCR4-tropic virus entry, but not CXCR4-independent endocytosis or post-entry steps. When tested against a panel of clinical isolates, TIQ-15 showed potent inhibition against CXCR4-tropic and dual-tropic viruses, and moderate inhibition against CCR5-tropic isolates. This observation was followed by a co-dosing study with maraviroc, and TIQ-15 demonstrated synergistic activity. In summary, here we describe a novel HIV-1 entry inhibitor, TIQ-15, which potently inhibits CXCR4-tropic viruses while possessing low-level synergistic activities against CCR5-tropic viruses. TIQ-15 could potentially be co-dosed with the CCR5 inhibitor maraviroc to block viruses of mixed tropisms. Author summary: HIV uses the chemokine co-receptors CXCR4 or CCR5 for cell fusion and entry. While the CCR5-tropic viruses predominate early in HIV infection, the emergence of the CXCR4-tropic viruses at later stages in 50% of patients is associated with rapid disease progression. The CCR5 antagonist maraviroc has been approved for treating HIV infection. However, currently, there is no clinical anti-HIV CXCR4 inhibitor. Here we report a novel CXCR4 antagonist TIQ-15 that potently blocked CXCR4-tropic HIV infection of human CD4 T cells. TIQ-15 in combination with maraviroc also demonstrated synergistic activities against CCR5-tropic viruses and could be potentially used with maraviroc to block viruses of mixed tropisms. [ABSTRACT FROM AUTHOR]- Published
- 2024
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3. Effect of Wei Qi Booster on immune and anti-oxidative function in aged mice.
- Author
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Shuang Ma, Yuming Chen, Zhilong Zhou, and Aituan Ma
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CHINESE medicine ,BODY weight ,CD8 antigen ,CD4 antigen ,JEJUNUM - Abstract
This research was conducted to examine the impact of Wei Qi Booster (WQB) on immune parameters and anti-oxidative function in aged mice. Fifty aged mice were randomly assigned to five different groups. Group A was designated as the control group. Mice in Group B were receiving Levamisole at 10 mg/kg body weight. Each mouse in groups C, D and E received 0.1, 1, and 2% WQB, respectively. Another ten young mice, designated as group F, were fed regularly. The mice were fed according to the above methods for 28 days. Results showed that relative to the control group, the body weight and immune organs indexes experienced a substantial rise in the group with 1% WQB. In addition, 1% WQB could improve the activity of SOD and reduce the MDA levels. Expressions of CD4 and sIgA increased while CD8 decreased in the jejunum of aged mice treated with WQB. IL2 and IFN-γ levels increased in the 1% WQB group, showing no notable difference compared to the young mice group. The results demonstrated that WQB can elevate immune levels and enhance anti-oxidative functions in aged mice. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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4. ASM is a therapeutic target in dermatomyositis by regulating the differentiation of naive CD4 + T cells into Th17 and Treg subsets.
- Author
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Chen, Yuehong, Liu, Huan, Luo, Zhongling, Zhang, Jiaqian, Dong, Min, Yin, Geng, and Xie, Qibing
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T helper cells ,T cells ,REGULATORY T cells ,DERMATOMYOSITIS ,CD4 antigen - Abstract
Background: This study aims to investigate the involvement of acid sphingomyelinase (ASM) in the pathology of dermatomyositis (DM), making it a potential therapeutic target for DM. Methods: Patients with DM and healthy controls (HCs) were included to assess the serum level and activity of ASM, and to explore the associations between ASM and clinical indicators. Subsequently, a myositis mouse model was established using ASM gene knockout and wild-type mice to study the significant role of ASM in the pathology and to assess the treatment effect of amitriptyline, an ASM inhibitor. Additionally, we investigated the potential treatment mechanism by targeting ASM both in vivo and in vitro. Results: A total of 58 DM patients along with 30 HCs were included. The ASM levels were found to be significantly higher in DM patients compared to HCs, with median (quartile) values of 2.63 (1.80–4.94) ng/mL and 1.64 (1.47–1.96) ng/mL respectively. The activity of ASM in the serum of DM patients was significantly higher than that in HCs. Furthermore, the serum levels of ASM showed correlations with disease activity and muscle enzyme levels. Knockout of ASM or treatment with amitriptyline improved the severity of the disease, rebalanced the CD4 T cell subsets Th17 and Treg, and reduced the production of their secreted cytokines. Subsequent investigations revealed that targeting ASM could regulate the expression of relevant transcription factors and key regulatory proteins. Conclusion: ASM is involved in the pathology of DM by regulating the differentiation of naive CD4 + T cells and can be a potential treatment target. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Ultrapotent Broadly Neutralizing Human‐llama Bispecific Antibodies against HIV‐1.
- Author
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Xu, Jianliang, Zhou, Tongqing, McKee, Krisha, Zhang, Baoshan, Liu, Cuiping, Nazzari, Alexandra F., Pegu, Amarendra, Shen, Chen‐Hsiang, Becker, Jordan E., Bender, Michael F., Chan, Payton, Changela, Anita, Chaudhary, Ridhi, Chen, Xuejun, Einav, Tal, Kwon, Young Do, Lin, Bob C., Louder, Mark K., Merriam, Jonah S., and Morano, Nicholas C.
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BISPECIFIC antibodies ,MONOCLONAL antibodies ,HIV ,CD4 antigen ,IMMUNOGLOBULINS - Abstract
Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV‐1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion‐stabilized HIV‐1 envelope (Env) trimer, BG505 DS‐SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4‐binding site (CD4bs) of vulnerability. Two of the vaccine‐elicited CD4bs‐targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a‐hinge region and human IgG1‐constant region (G36×3‐IgG2a and R27×3‐IgG2a), neutralized 96% of a multiclade 208‐strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL−1, respectively. Cryo‐EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV‐1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2‐apex‐targeting broadly neutralizing antibody, CAP256V2LS. The resultant human‐llama bispecific antibody CAP256L‐R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV‐1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn‐Fc mice similar to the parent CAP256V2LS. Vaccine‐elicited llama nanobodies, when combined with V2‐apex broadly neutralizing antibodies, may therefore be able to fulfill anti‐HIV‐1 therapeutic and prophylactic clinical goals. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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6. MHC heterozygosity limits T cell receptor variability in CD4 T cells.
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Brown, Alexander J., White, Janice, Shaw, Laura, Gross, Jimmy, Slabodkin, Andrei, Kushner, Ella, Greiff, Victor, Matsuda, Jennifer, Gapin, Laurent, Scott-Browne, James, Kappler, John, and Marrack, Philippa
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T cell receptors ,T cells ,CD4 antigen ,GENETIC code ,THYMOCYTES - Abstract
αβ T cell receptor (TCR) V(D)J genes code for billions of TCR combinations. However, only some appear on peripheral T cells in any individual because, to mature, thymocytes must react with low affinity but not high affinity with thymus expressed major histocompatibility (MHC)/peptides. MHC proteins are very polymorphic. Different alleles bind different peptides. Therefore, any individual might express many different MHC alleles to ensure that some peptides from an invader are bound to MHC and activate T cells. However, most individuals express limited numbers of MHC alleles. To explore this, we compared the TCR repertoires of naïve CD4 T cells in mice expressing one or two MHC alleles. Unexpectedly, the TCRs in heterozygotes were less diverse that those in the sum of their MHC homozygous relatives. Our results suggest that thymus negative selection cancels out the advantages of increased thymic positive selection in the MHC heterozygotes. Editor's summary: T cells undergo positive and negative selection in the thymus through T cell receptor (TCR) recognition of peptides presented on major histocompatibility (MHC) proteins. Although the genes encoding MHC proteins are among the most polymorphic, most vertebrates individually express relatively few MHC alleles. How the number of MHC alleles expressed affects thymic selection and the TCR repertoire on an individual level remains unclear. Using mice expressing different MHC loci on the same background, Brown et al. compared the TCR repertoires of naïve CD4 T cells from MHC homozygous and heterozygous mice. MHC heterozygotes expressed a less diverse TCR repertoire than expected compared with their MHC homozygous relatives, likely because of increased rates of negative selection. These findings suggest that the number of MHC alleles expressed in an individual animal has been evolutionarily optimized to minimize "holes" in the TCR repertoire. —Claire Olingy [ABSTRACT FROM AUTHOR]
- Published
- 2024
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7. The interaction between the costimulatory molecules CD80/86 and CD28 contributed to CD4+ T lymphocyte activation in flounder (Paralichthys olivaceus).
- Author
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Xing, Jing, Hu, Yujie, Liu, Wenjing, Tang, Xiaoqian, Sheng, Xiuzhen, Chi, Heng, and Zhan, Wenbin
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T cells , *CD28 antigen , *LYMPHOCYTE transformation , *PARALICHTHYS , *CD4 antigen , *RECOMBINANT proteins , *T cell receptors - Abstract
CD28 and CD80/86 are crucial co-stimulatory molecules for the T cell activation. Previous study illustrated that CD28 and CD80/86 present on T cells and antigen-presenting cells in flounder (Paralichthys olivaceus), respectively. The co-stimulatory molecules were closely associated with cell immunity. In this paper, recombinant protein of flounder CD80/86 (rCD80/86) and phytohemagglutinin (PHA) were added to peripheral blood leukocytes (PBLs) in vitro. Lymphocytes were significantly proliferated with CFSE staining, and the proportion of CD4+ and CD28+ lymphocytes significantly increased. In the meantime, genes related to the CD28-CD80/86 signaling pathway or T cell markers were significantly upregulated (p < 0.05). For further study, the interaction between CD80/86 and CD28 was confirmed. The plasmid of CD28 (pCD28-FLAG and pVN-CD28) or CD80/86 (pVC-CD80/86) was successfully constructed. In addition, pVN-ΔCD28 without the conserved motif "TFPPPF" was constructed. The results showed that bands of pCD28-FLAG bound to rCD80/86 were detected by both anti-FLAG and anti-CD80/86. pVN-CD28 complemented to pVC-CD80/86 showing positive fluorescent signals, and pVN-ΔCD28 failed to combine with pVC-CD80/86. The motif "TFPPPF" in CD28 played a crucial role in this linkage. These results indicate that CD28 and CD80/86 molecules interact with each other, and their binding may modulate T lymphocytes immune response in flounder. This study proved the existence of CD28-CD80/86 signaling pathway in flounder. • RCD80/86 and PHA induced lymphocyte proliferation and proportion of CD4+ cells in flounder. • RCD80/86 and PHA upregulated the expression of B7-CD28 signaling pathway genes, T cell markers, and cytokines. • PCD28-FLAG bound to rCD80/86, and pVN-CD28 complemented to pVC-CD80/86 in vitro. • Motif of "TFPPPF" in CD28 plays crucial role in the interaction between CD28 and CD80/86. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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8. Memory CD8 T cells are vulnerable to chronic IFN-γ signals but not to CD4 T cell deficiency in MHCII-deficient mice.
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Setoguchi, Ruka, Sengiku, Tomoya, Kono, Hiroki, Kawakami, Eiryo, Kubo, Masato, Yamamoto, Tadashi, and Hori, Shohei
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IMMUNOLOGIC memory ,T cells ,CD4 antigen ,INTERFERON receptors ,MICE - Abstract
The mechanisms by which the number of memory CD8 T cells is stably maintained remains incompletely understood. It has been postulated that maintaining them requires help from CD4 T cells, because adoptively transferred memory CD8 T cells persist poorly in MHC class II (MHCII)-deficient mice. Here we show that chronic interferon-γ signals, not CD4 T cell-deficiency, are responsible for their attrition in MHCII-deficient environments. Excess IFN-γ is produced primarily by endogenous colonic CD8 T cells in MHCII-deficient mice. IFN-γ neutralization restores the number of memory CD8 T cells in MHCII-deficient mice, whereas repeated IFN-γ administration or transduction of a gain-of-function STAT1 mutant reduces their number in wild-type mice. CD127
high memory cells proliferate actively in response to IFN-γ signals, but are more susceptible to attrition than CD127low terminally differentiated effector memory cells. Furthermore, single-cell RNA-sequencing of memory CD8 T cells reveals proliferating cells that resemble short-lived, terminal effector cells and documents global downregulation of gene signatures of long-lived memory cells in MHCII-deficient environments. We propose that chronic IFN-γ signals deplete memory CD8 T cells by compromising their long-term survival and by diverting self-renewing CD127high cells toward terminal differentiation. Memory CD8+ T cells persist poorly in MHCII-deficient mice. Here the authors show that this CD8+ T cell attrition is not caused by a lack of CD4+ T cell help, as previously proposed, but by chronic IFN-γ signals derived from endogenous colonic CD8+ T cells. [ABSTRACT FROM AUTHOR]- Published
- 2024
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9. Tissue adaptation of CD4 T lymphocytes in homeostasis and cancer.
- Author
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Pereira, Marina V. A., Galvani, Rômulo G., Gonçalves-Silva, Triciana, Meira de Vasconcelo, Zilton Farias, and Bonomo, Adriana
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T cells ,HOMEOSTASIS ,CD4 antigen ,TISSUES ,CANCER invasiveness - Abstract
The immune system is traditionally classified as a defense system that can discriminate between self and non-self or dangerous and non-dangerous situations, unleashing a tolerogenic reaction or immune response. These activities are mainly coordinated by the interaction between innate and adaptive cells that act together to eliminate harmful stimuli and keep tissue healthy. However, healthy tissue is not always the end point of an immune response. Much evidence has been accumulated over the years, showing that the immune system has complex, diversified, and integrated functions that converge to maintaining tissue homeostasis, even in the absence of aggression, interacting with the tissue cells and allowing the functional maintenance of that tissue. One of the main cells known for their function in helping the immune response through the production of cytokines is CD4
+ T lymphocytes. The cytokines produced by the different subtypes act not only on immune cells but also on tissue cells. Considering that tissues have specific mediators in their architecture, it is plausible that the presence and frequency of CD4+ T lymphocytes of specific subtypes (Th1, Th2, Th17, and others) maintain tissue homeostasis. In situations where homeostasis is disrupted, such as infections, allergies, inflammatory processes, and cancer, local CD4+ T lymphocytes respond to this disruption and, as in the healthy tissue, towards the equilibrium of tissue dynamics. CD4+ T lymphocytes can be manipulated by tumor cells to promote tumor development and metastasis, making them a prognostic factor in various types of cancer. Therefore, understanding the function of tissue-specific CD4+ T lymphocytes is essential in developing new strategies for treating tissue-specific diseases, as occurs in cancer. In this context, this article reviews the evidence for this hypothesis regarding the phenotypes and functions of CD4+ T lymphocytes and compares their contribution to maintaining tissue homeostasis in different organs in a steady state and during tumor progression. [ABSTRACT FROM AUTHOR]- Published
- 2024
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10. Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.
- Author
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Kumar, Ajay, Chenxian Ye, Nkansah, Afia, Decoville, Thomas, Fogo, Garrett M., Sajjakulnukit, Peter, Reynolds, Mack B., Li Zhang, Quaye, Osbourne, Young-Ah Seo, Sanderson, Thomas H., Lyssiotis, Costas A., and Cheong-Hee Chang
- Subjects
T cells ,IRON in the body ,CD4 antigen ,METABOLISM ,CELL physiology - Abstract
In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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11. The trajectories of CD4 T lymphocytes over time in patients who have defaulted on treatment for tuberculosis in a cohort of people living with HIV, Recife/PE.
- Author
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Cunha, Rossana, Filho, Demócrito de B. M., M. Albuquerque, Maria de Fátima P., Lacerda, Heloísa R., Diniz, George T. N., Montarroyos, Ulisses R., Rodrigues, Laura C., Vilela Moura, Líbia Cristina R., and Ximenes, Ricardo A. A.
- Subjects
TUBERCULOSIS patients ,HIV-positive persons ,T cells ,CD4 lymphocyte count ,CD4 antigen ,CLINICAL decision support systems - Abstract
Background: The CD4 T lymphocyte count in people living with HIV (PLHIV) is a predictor for the progression of the disease (AIDS), survival and response to antiretroviral treatment (ART). A CD4 T lymphocyte count of less than 200 cells/mm3 is indicative of a greater risk for the onset of opportunistic diseases and death. Defaulting on treatment for tuberculosis (TB) may impact immune recovery in PLHIV who are taking ART. The aim of this study was to investigate an association of the CD4 lymphocyte with TB treatment Trajectory and with death. Methods: A cohort of PLHIV over eighteen years of age and who were taking ART and who had defaulted on pulmonary TB treatment. Latent Class analysis was used to identify different trajectories of CD4 T lymphocyte counts over time. Results: Latent class 1 (High CD4 trajectory) grouped individuals together who were characterized as maintaining a low probability (0 to 29%) of a CD4 count ≤ 200 cells/mm
3 over time, while latent class 2 (Low CD4 trajectory) grouped individuals together with a high probability (93% to 60%), and latent class 3 (Fluctuating CD4 trajectory), grouped individuals with a fluctuating probability (66% to 0%). The chance of defaulting on treatment earlier (≤ 90 days) was four times higher in latent class 2 (Low CD4 trajectory). Although there was no statistical significance, there was a higher frequency of deaths in this same latent class. Conclusion: Individuals with a high probability of a CD4 count ≤ 200 cells/ mm3 should be monitored in order to avoid treatment default and thereby prevent death. New studies should be conducted with a larger sample size and a longer follow-up time in PLHIV who initiated ART treatment early so as to support clinical decisions for a better understanding of immune behavior. [ABSTRACT FROM AUTHOR]- Published
- 2024
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12. TCR Δ chain repertoire characteristic between healthy human CD4+ and CD8+ T cells.
- Author
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Ge Li, Yaqiong Chen, Yinji Liu, Zhenfang Gao, Ruiyan Jia, Zhonglin Lv, Yuxiang Li, Zhiding Wang, and Gencheng Han
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T cell receptors ,T cells ,CD8 antigen ,CD4 antigen ,HLA histocompatibility antigens ,MAJOR histocompatibility complex ,PEPTIDES - Abstract
T cell is vital in the adaptive immune system, which relays on T-cell receptor (TCR) to recognize and defend against infection and tumors. T cells are mainly divided into well-known CD4+ and CD8+ T cells, which can recognize short peptide antigens presented by major histocompatibility complex (MHC) class II and MHC class I respectively in humoral and cell-mediated immunity. Due to the Human Leukocyte Antigen (HLA) diversity and restriction with peptides complexation, TCRs are quite diverse and complicated. To better elucidate the TCR in humans, the present study shows the difference between the TCR repertoire in CD4+ and CD8+ T cells from 30 healthy donors. The result showed count, clonality, diversity, frequency, and VDJ usage in CD4+ and CD8+ TCR-β repertoire is different, but CDR3 length is not. The Common Clone Cluster result showed that CD4+ and CD8+ TCR repertoires are connected separately between the bodies, which is odd considering the HLA diversity. More knowledge about TCR makes more opportunities for immunotherapy. The TCR repertoire is still a myth for discovery. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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13. A hepatic network of dendritic cells mediates CD4 T cell help outside lymphoid organs.
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English, Kieran, Kwan, Rain, Holz, Lauren E., McGuffog, Claire, Krol, Jelte M. M., Kempe, Daryan, Kaisho, Tsuneyasu, Heath, William R., Lisowski, Leszek, Biro, Maté, McCaughan, Geoffrey W., Bowen, David G., and Bertolino, Patrick
- Subjects
T cells ,DENDRITIC cells ,LIVER cells ,CD4 antigen ,LYMPHOID tissue ,IMMUNOLOGIC memory - Abstract
While CD4
+ T cells are a prerequisite for CD8+ T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8+ T cells are unknown. Here, we developed an experimental system to investigate cognate CD4+ and CD8+ T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4+ and CD8+ T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4+ T cells and expand the number of CD8+ T cells in situ, resulting in larger effector and memory CD8+ T cell pools. These findings reveal that CD4+ T cells promote intrahepatic immunity by amplifying the CD8+ T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions. Here, English et al. show that after expanding in lymphoid tissues, CD4+ and CD8+ T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4+ T cells locally license hepatic dendritic cells and further expand CD8+ T cell numbers. [ABSTRACT FROM AUTHOR]- Published
- 2024
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14. Late-rising CD4 T cells resolve mouse cytomegalovirus persistent replication in the salivary gland.
- Author
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Brunel, Simon, Picarda, Gaelle, Gupta, Ankan, Ghosh, Raima, McDonald, Bryan, El Morabiti, Rachid, Jiang, Wenjin, Greenbaum, Jason A., Adler, Barbara, Seumois, Gregory, Croft, Michael, Vijayanand, Pandurangan, and Benedict, Chris A.
- Subjects
T cells ,CYTOMEGALOVIRUSES ,SALIVARY glands ,CD4 antigen ,IMMUNOLOGIC memory ,VIRAL proteins ,IMMUNOSENESCENCE - Abstract
Conventional antiviral memory CD4 T cells typically arise during the first two weeks of acute infection. Unlike most viruses, cytomegalovirus (CMV) exhibits an extended persistent replication phase followed by lifelong latency accompanied with some gene expression. We show that during mouse CMV (MCMV) infection, CD4 T cells recognizing an epitope derived from the viral M09 protein only develop after conventional memory T cells have already peaked and contracted. Ablating these CD4 T cells by mutating the M09 genomic epitope in the MCMV Smith strain, or inducing them by introducing the epitope into the K181 strain, resulted in delayed or enhanced control of viral persistence, respectively. These cells were shown to be unique compared to their conventional memory counterparts; producing higher IFNγ and IL-2 and lower IL-10 levels. RNAseq analyses revealed them to express distinct subsets of effector genes as compared to classical CD4 T cells. Additionally, when M09 cells were induced by epitope vaccination they significantly enhanced protection when compared to conventional CD4 T cells alone. These data show that late-rising CD4 T cells are a unique memory subset with excellent protective capacities that display a development program strongly differing from the majority of memory T cells. Author summary: Functional memory T cells are critical to ultimately control chronic viral infection. We show that cytomegalovirus (CMV) induces a population of unique memory CD4 T cells that expand late during infection and resolve viral persistence much better than conventional T memory cells. Mutation of the genomic CMV epitope recognized by these T cells results in markedly enhanced persistent replication, and introduction of the epitope into a CMV strain that lacks it induces much quicker resolution of persistence. When induced via vaccination, we show these T cells provide significantly enhanced protection against acute viral challenge. Together our study identifies a novel population of CD4 T cells that utilize distinct effector function(s) to rapidly resolve persistent viral replication. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
15. Aqueous black rice (Oryza sativa L. indica) extract enhanced the activation of CD4+ and CD8+ T cells in mouse breast cancer model.
- Author
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Hartati, Fadjar Kurnia, Nafisah, Wirdatun, Sutanto, Adi, Saati, Elfi Anis, Khairoh, Miftahul, and Sjamsiah
- Subjects
RICE yields ,CD4 antigen ,BREAST cancer treatment ,THERAPEUTIC use of antineoplastic agents ,PLANT extracts - Abstract
Black rice is a functional food of Indonesia that has several pharmaceutical activities including anti-cancer. This study aimed to evaluate the immunomodulatory potential of aqueous black rice (ABR) extract on mouse breast cancer model. A carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA), was applied for breast cancer induction in mice. The study was designed to be seven groups (six mice in each group), including Normal or control group (N), a Cancer (C; DMBA-induced mice) group, Cisplatin (Cis; DMBA-induced mice + Cisplatin) treatment group, and DMBA-induced mice + ABR extract (ABR1; dose 1 or 0.2 g/kg, ABR2; dose 2 or 0.3 g/kg, ABR3; dose 3 or 0.4 g/kg, and ABR4; dose 4 or 0.5 g/kg) treatment group. The cancer-bearing mice were given ABR extract for two weeks, and flow cytometry was used to assess the numbers of CD4
+ and CD8+ T cells, as well as the production of inflammatory cytokines IL-17, TNFα, and IFNγ. The histopathology of breast tissue in mice was analyzed using hematoxylin and eosin staining and microscope observation. The induction of DMBA in mice lower the activation of CD4+ and CD8+ T cells, and induced IL-17, TNFα, and IFNγ production. The histology of the mammary tissue of the untreated mice demonstrated an infiltration of cancer cells toward stroma, whereas that of the treated groups, especially those under high doses of ABR extract, showed a better prognosis, exhibiting a reduction in cancer cells surrounded by a relatively larger number of adipose tissues. The activation of CD4+ and CD8+ T cells, as well as the reduction of cytokines (IL-17, TNFα, and IFNγ), were thought to be influenced by ABR extract. The activation of T cells optimized the elimination of cancer cells activity; moreover, the production of pro-tumor cytokines was inhibited. [ABSTRACT FROM AUTHOR]- Published
- 2024
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- View/download PDF
16. Effect of Topical Programmed Death-Ligand1 on Corneal Epithelium in Dry Eye Mouse.
- Author
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Lee, Ko Eun, Oh, Seheon, Bhujel, Basanta, Kim, Chang Min, Lee, Hun, Park, Jin Hyoung, and Kim, Jae Yong
- Subjects
SCOPOLAMINE ,MEIBOMIAN glands ,PROGRAMMED death-ligand 1 ,DRY eye syndromes ,CORNEA ,CD4 antigen ,LACRIMAL apparatus - Abstract
Dry eye disease (DED) is a growing health concern that impacts millions of individuals every year, and is associated with corneal injury, excessive oxidative stress and inflammation. Current therapeutic strategies, including artificial tears and anti-inflammatory agents, are unable to achieve a permanent clinical cure due to their temporary nature or adverse side effects. Therefore, here, we investigated the effectiveness of the topical administration of programmed death-ligand 1 (PD-L1) in the mouse model of DED. The model was generated in C57BL/6 mice by excising the extra orbital lacrimal gland and causing desiccation stress with scopolamine injections. Subsequently, either phosphate-buffered saline (3 µL/eye) or PD-L1 (0.5 µg/mL) was topically administered for 10 days. Tear volume was evaluated with phenol red thread, and corneal fluorescein staining was observed to quantify the corneal epithelial defect. Corneas were collected for histological analysis, and the expression levels of inflammatory signaling proteins such as CD4, CD3e, IL-17, IL-1β, pIkB-α, pNF-kB and pERK1/2 were assessed through immunofluorescence and Western blot techniques. Our results demonstrate that desiccating stress-induced corneal epithelial defect and tear secretion were significantly improved by topical PD-L1 and could reduce corneal CD4+ T cell infiltration, inflammation and apoptosis in a DED mouse model by downregulating IL-17 production and ERK1/2-NFkB pathways. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
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