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Bullous pemphigoid (BP) is an organ-specific disease. Its pathogenesis has not been clearly studied yet; However, studies in recent years have shown that its pathogenesis is related to T helper cells. The pathogenesis of BP is mainly related to Th2 and Th17-related cytokines. IL-4, IL-5 and IL-13 cause eosinophil recruitment, promote antibody production, trigger pruritus and promote blister formation and other symptoms. IL-17 and IL-23 promote the production of matrix metalloproteinase-9 (MMP-9) by related cells, which causes dermo-epidermal junction (DEJ) separation to form bullae and blisters, and can persist in BP inflammation. The serum concentrations of IL-17 and IL-23 are related to the prognosis of BP. In this paper, we focus on the role of related cytokines in the pathogenesis of bullous pemphigoid and the relationship between the related cytokine populations secreted by three major T helper cells—helper T lymphocytes 1 (Th1), Th2, and Th17. A better understanding of the biological and immunological functions of cytokines associated with BP patients will provide opportunities for therapeutic targets in BP. [ABSTRACT FROM AUTHOR]

The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers pubished in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers published in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. [ABSTRACT FROM AUTHOR]

Simple Summary: Every year, cervical cancer affects more than 500,000 women worldwide. The persistent infection caused by the human papillomavirus (HPV) is the main risk factor for the development of this type of cancer. Conventional treatments for cervical cancer are often associated with resistance and side effects. Therefore, it is necessary to find new targets for the development of more effective therapeutic approaches. In recent years, an increasing number of studies have been concerned with developing immunotherapeutic strategies for treating cancer. Thus, it is important to investigate new targets, such as the various molecules and cells that are involved in the cancer-immunity cycle (CIC). This process consists of the release of cancer antigens and their destruction by cytotoxic T-cells. Hence, in this review, we discuss the molecular changes that occur at each stage of the CIC for cervical cancer, including the impact of variables such as histological subtype and HPV infection. Moreover, we explore the latest immunotherapeutic approaches that have been adopted, together with their benefits and limitations. In this scenario, current studies are opening up new horizons in clinical practice for a personalized treatment of cervical cancer. Cervical cancer (CC) is the fourth most common cancer in women worldwide, with more than 500,000 new cases each year and a mortality rate of around 55%. Over 80% of these deaths occur in developing countries. The most important risk factor for CC is persistent infection by a sexually transmitted virus, the human papillomavirus (HPV). Conventional treatments to eradicate this type of cancer are accompanied by high rates of resistance and a large number of side effects. Hence, it is crucial to devise novel effective therapeutic strategies. In recent years, an increasing number of studies have aimed to develop immunotherapeutic methods for treating cancer. However, these strategies have not proven to be effective enough to combat CC. This means there is a need to investigate immune molecular targets. An adaptive immune response against cancer has been described in seven key stages or steps defined as the cancer-immunity cycle (CIC). The CIC begins with the release of antigens by tumor cells and ends with their destruction by cytotoxic T-cells. In this paper, we discuss several molecular alterations found in each stage of the CIC of CC. In addition, we analyze the evidence discovered, the molecular mechanisms and their relationship with variables such as histological subtype and HPV infection, as well as their potential impact for adopting novel immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Exercise training is not only a necessary means to improve the level of exercise, but also an important means to improve the body's immunity. Different time, intensity, items, and forms of exercise training have different effects on the body's immune function. As a double-edged sword to improve the body's immune function, exercise training is a different reaction mechanism of different immune cells after exercise training. This paper combined with foreign scholars' studies on the immune function of the body of literature from different exercise intensity, different time, different sports, different movement forms, and different external environment such as angle of view for athletes body's immune cells and humoral immunity summarized the various indexes such as combing, in order to help academia, medicine, and sports. It provides enlightenment to the contemporary public on how to participate in sports training more healthily. [ABSTRACT FROM AUTHOR]

Trillions of microorganisms exist in the human intestine as commensals and contribute to homeostasis through their interactions with the immune system. In this review, we use previous evidence from published papers to elucidate the involvement of commensal-specific T cells (CSTCs) in regulating intestinal inflammatory responses. CSTCs are generated centrally in the thymus or peripherally at mucosal interfaces and present as CD4+ or CD8+ T cells. Bacteria, fungi, and even viruses act commensally with humans, warranting consideration of CSTCs in this critical relationship. Dysregulation of this immunological balance can result in both intestinal inflammation or damaging autoimmune responses elsewhere in the body. Given the relative novelty of CSTCs in the literature, we aim to introduce the importance of their role in maintaining immune homeostasis at barrier sites such as the intestine. [ABSTRACT FROM AUTHOR]

Based on the results of recent research in the field and Part 1 of this article (in this issue), the present paper will discuss the protective and destructive aspects of the T-cellmediated adaptive immunity associated with the bacterial virulent factors or antigenic determinants during periodontal pathogenesis. Attention will be focused on: (i) osteoimmunology and periodontal disease; (ii) some molecular techniques developed and applied to identify critical microbial virulence factors or antigens associated with host immunity (with Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis as the model species); and (iii) summarizing the identified virulence factors/antigens associated with periodontal immunity. Thus, further understanding of the molecular mechanisms of the host's T-cell-mediated immune responses and the critical microbial antigens related to disease pathogenesis will facilitate the development of novel therapeutics or protocols for future periodontal treatments. Abbreviations used in the paper are as follows: A. actinomycetemcomitans (Aa), Actinobacillus actinomycetemcomitans; Ab, antibody; DC, dendritic cells; mAb, monoclonal antibody; pAb, polyclonal antibody; OC, osteoclast; PAMP, pathogen-associated molecular patterns; P. gingivalis (Pg), Porphyromonas gingivalis; RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand; OPG, osteoprotegerin; TCR, T-cellreceptors; TLR, Toll-like receptors. [ABSTRACT FROM AUTHOR]

The spleen is a complex secondary lymphoid organ that plays a crucial role in controlling blood‐stage infection with Plasmodium parasites. It is tasked with sensing and removing parasitized RBCs, erythropoiesis, the activation and differentiation of adaptive immune cells, and the development of protective immunity, all in the face of an intense inflammatory environment. This paper describes how these processes are regulated following infection and recognizes the gaps in our current knowledge, highlighting recent insights from human infections and mouse models. [ABSTRACT FROM AUTHOR]

In this paper, we consider an improved Human T-lymphotropic virus type I (HTLV-I) infection model with the mitosis of CD4+ T cells and delayed cytotoxic T-lymphocyte (CTL) immune response by analyzing the distributions of roots of the corresponding characteristic equations, the local stability of the infection-free equilibrium, the immunity-inactivated equilibrium, and the immunity-activated equilibrium when the CTL immune delay is zero is established. And we discuss the existence of Hopf bifurcation at the immunity-activated equilibrium. We define the immune-inactivated reproduction ratio R0 and the immune-activated reproduction ratio R1. By using Lyapunov functionals and LaSalle's invariance principle, it is shown that if R0 < 1, the infection-free equilibrium is globally asymptotically stable; if R1 < 1 < R0, the immunityinactivated equilibrium is globally asymptotically stable; if R1 > 1, the immunity-activated equilibrium is globally asymptotically stable when the CTL immune delay is zero. Besides, uniform persistence is obtained when R1 > 1. Numerical simulations are carried out to illustrate the theoretical results. [ABSTRACT FROM AUTHOR]

Background: Synovitis is an inflammation-related disease linked to rheumatoid arthritis, osteoarthritis, infections and trauma. This inflammation is accompanied by immune cells infiltration which initiates an inflammatory response causing pain, discomfort and affecting the normal joint function. The treatment of synovitis is based on the administration of anti-inflammatory drugs or biological agents such as platelet rich plasma and mesenchymal stem cells. However, the evaluation and validation of more effective therapies of synovitis requires the establishment of clinically relevant animal models. Results: In this study, Large White pigs were pre-immunized to evaluate an antigen-induced synovitis. The immune monitoring of synovial fluids in this model allowed us the identification of IL-12p40 and T cell subsets as immune biomarkers. Moreover, the evolution of synovitis was performed by arthroscopic procedures and kinetic analysis. In summary, this paper describes an animal model of antigen-induced synovitis to be used in the evaluation of anti-inflammatory therapies. Conclusions: The novelty of this paper lies in the development of a clinically relevant model of synovitis which permits the simultaneous evaluation of synovitis from an immunological, surgical and kinetic point of view. [ABSTRACT FROM AUTHOR]

Background: In December of 2019, coronavirus disease 2019 (Covid-19) was reported in Wuhan, China, and has now rapidly swept around the world. Much research has been carried out since the outbreak, but few studies have focused on the dysfunction of the adaptive immunity. Methods: In this retrospective and multi-center study, 373 patients with laboratory-confirmed COVID-19 from Shanghai Public Health Clinical Center and Affiliated Hospital of Putian University were recruited. Demographic, clinical, radiological features, and laboratory data were recorded and analyzed at admission and at discharge. Results of immunological tests were followed up until the patients were discharged. Results: Of the 373 patients with COVID-19 pneumonia, 322 were in the non-severe group and 51 were in the severe group. Number of T cells, CD4+ and CD8+ T cells, and total lymphocytes declined remarkably upon admission and elevated when the patients were discharged. At admission, counts of total lymphocytes, T cells, CD4+ and CD8+ T cells, and levels of C3 and C4 in the severe group were lower than those in the non-severe group, whereas the neutrophil to lymphocyte ratio (NLR) was higher in the severe group. Counts of T cells, CD4+ and CD8+ T cells, and total lymphocytes were negatively correlated with lactate dehydrogenase and C-reactive protein. Conclusion: COVID-19 might target adaptive immunity and cause a decrease in lymphocytes, especially T cells and subsets. Physicians should pay close attention to the adaptive immunity of patients upon admission. Monitoring NLR, T lymphocytes, and subsets would help physicians with the proper diagnosis and treatment of COVID-19. The reviews of this paper are available via the supplemental material section. [ABSTRACT FROM AUTHOR]

Aim: The objective of this review is to describe the immunological mechanisms which facilitate maternal tolerance at the maternal‐placental interface, and to discuss how these mechanisms are disrupted in pre‐eclampsia. Methods: A literature review was performed based on the analysis of papers available on PubMed. The most important and relevant studies regarding the immunological mechanisms which facilitate maternal tolerance in healthy pregnancy and pre‐eclampsia are presented in this article. Results: The maternal‐placental interface is the site where the immune tolerance begins and develops. Within the innate immunity, natural killer cells, macrophages and dendritic cells play a pivotal role in tolerance through regulation of inflammation. On the other hand, within the adaptive immunity, the correct increase of regulatory T cells is crucial for ensuring immune tolerance toward placental cells. Disturbances in maternal tolerance can lead to the appearance of pregnancy complications such as pre‐eclampsia, which has a considerable impact on perinatal morbidity and mortality. Conclusion: Our partial knowledge of immunological mechanisms involved in tolerance at the maternal‐placental interface indicates that pre‐eclampsia is characterized by alterations of this maternal immune tolerance, which could represent the origin of the disease. [ABSTRACT FROM AUTHOR]

Cutaneous leishmaniasis (CL) is a major public health problem worldwide and spreads to human via the bite of sand flies during blood meal. Following its inoculation, the promastigotes are immediately taken up by phagocytic cells and these leishmania-infected host cells produce proinflammatory cytokines that activate other immune cells and these infected host cells produce more cytokines and reactive nitrogen and oxygen species for efficient control of leishmania infection. Many experimental studies showed that resistance to infection with leishmania paraites is associated with the production of proinflammatory cytokines and activation of CD4+ Th1 response. On the other hand, vulnerability to this parasitic infection is correlated to production of T helper 2 cytokines that facilitate persistence of parasites and disease progression. In addition, some studies have also indicated that CD8+ T cells play a vital role in immune defense through cytokine production and their cytotoxic activity and excessive production of proinflammatory mediators promote amplified recruitment of cells. This could be correlated with excessive inflammatory reaction and ultimately resulted in tissue destruction and development of immunopathogenesis. Thus, there are contradictions regarding the role of immune responses in protection and immunopathogenesis of CL disease. Therefore, the aim of this paper was to review the role of host immune response in protection and its contribution to disease severity for CL infection. In order to obtain more meaningful data regarding the nature of immune response to leishmania, further in-depth studies focused on immune modulation should be conducted to develop better therapeutic strategies. [ABSTRACT FROM AUTHOR]

Leukemia is a malignant cancer of the blood. It is the most common type of cancer in children. In this paper, a mathematical model of leukemia in terms of ordinary differential equations has been developed. We propose a model to study the spread of leukemia by considering the effect of adoptive T cell therapy. The disease dynamics are given by a system of ordinary nonlinear differential equations that describe the interaction among susceptible blood cells, infected blood cells, cancer cells, and immune cells. The model is analyzed by using the stability theory of nonlinear differential equations and numerical simulations. A major goal of this work is to determine the spread of leukemia after applying the adoptive T cell therapy. We have observed that the system is stable locally and globally if stimulation rate or antigenicity rate of immune cells is greater than a threshold value dependent on the density of immune cells in the blood. We have also observed that the external reinfusion of immune cells by adoptive T cell therapy reduces the concentration of cancer cells and infected cells in the blood, which implies that immune cells kill cancer cells after being stimulated in the body. [ABSTRACT FROM AUTHOR]

Impaired regulation of immune function characterised by chronic inflammation together with a declining protective immune response is a major challenge to healthy ageing. It is therefore important to understand the mechanisms that regulate immune function and the impact of ageing upon such processes. Appropriate induction and resolution of the immune response require adequate availability of polyunsaturated fatty acids (PUFAs) for incorporation into cell membranes. However, humans are unable to synthesise PUFAs de novo and are dependent upon dietary intake for pre‐formed PUFAs or synthesis by the liver from the essential fatty acids, linoleic acid (LA, 18:2n‐6) and alpha‐linolenic acid (aLNA, 18:3n‐3). We have shown that activation of peripheral blood mononuclear cells increases PUFA biosynthesis from essential fatty acids via a mechanism that involves altered epigenetic regulation of a key gene in the pathway. Moreover, induction of PUFA synthesis is directly involved in the regulation of lymphocyte activation and proliferation. The aim of the Biotechnology and Biological Sciences Research Council responsive mode award described in this paper, 'How does polyunsaturated fatty acid biosynthesis regulate T‐lymphocyte function?', is to determine how PUFA biosynthesis regulates T‐cell function and the effect of ageing on this process. The project will identify points of regulation in the biosynthetic pathway and how these might influence the capacity for up‐regulation of PUFA synthesis in older individuals. We will use stable isotope tracers of LA and aLNA to determine whether newly synthesised PUFAs are preferential substrates for synthesis of lipid mediators and whether they are involved in formation of membrane microdomains that mediate cell signalling. [ABSTRACT FROM AUTHOR]

The immune function of living bodies has gained attention in engineering applications in a variety of fields. The authors proposed an immune network based on the immune response and researched its application to pattern recognition. The TH cell (helper T cell) that recognizes antigens in the immune response possesses diversity in order to fight various antigens and the function called interaction that communicates mutual information for correctly recognizing the antigens. The TH cell function successfully performs self-defense against unknown antigens. This paper proposes an immune network with the TH cell function added to an immune network we previously proposed. Specifically, we modeled the interaction and diversity functions of the TH cell in the matching process between input patterns and memory patterns. The proposed immune network is applied to a pattern recognition system of the alphabet and compared to a conventional method by numerical simulations. The proposed immune network exhibits lower incorrect recognition and rejections, and further improvement in the recognition rate over a conventional immune network by employing the process modeling the TH cell function. © 2005 Wiley Periodicals, Inc. Electron Comm Jpn Pt 3, 88(10): 12–22, 2005; Published online in Wiley InterScience (www.interscience. wiley.com). DOI 10.1002/ecjc.20162 [ABSTRACT FROM AUTHOR]

To develop new chemotherapeutics with anti-metastasis properties, a series of multi-specific niflumic acid (NFA) platinum(IV) complexes with DNA damage, inflammation inhibition, immunity activation, and angiogenesis suppression mechanisms were designed, synthesized and evaluated as novel antitumor agents. The dual NFA platinum(IV) complex with a cisplatin core showed promising antitumor activities both in vitro and in vivo with lower toxicity than platinum(II) drugs and displayed attractive anti-metastasis performance. It caused serious DNA damage and further elevated the expression of γ-H2AX. Furthermore, it promoted apoptosis by activating the mitochondrial apoptotic pathway and autophagy of tumor cells. Moreover, immune response in tumors was significantly improved by increasing CD3+, CD4+ and CD8+ T infiltrating cells. Subsequently, the pathway ERK/HIF-1α/VEGFA associated with angiogenesis was suppressed by the reduced inflammation and elevated immune response, and the density of microvessels marked by CD34 was significantly reduced in tumors. Accordingly, the multi-specific NFA platinum(IV) complexes have great potential to be developed as novel anti-proliferative and anti-metastatic drugs. [ABSTRACT FROM AUTHOR]

Introduction: Leprosy is a chronic infectious condition and the main cause of neuropathy that occurs brought on by M. leprae. It is known that the biological characteristics of the human host, such as the immunological ones, have a higher influence on the pathology of this disease than the intrinsic mechanisms of the bacterium. The objective of this work was to review the scientific knowledge about the relationship between immunopathology and the severity of leprosy. Methods: A systematic review following the PRISMA 2020 recommendations was conducted in the PUBMED, LILACS, SciELO and Science Direct databases using articles in English, Portuguese or Spanish between January 2011 and May 2022 with the descriptors "Leprosy/Immunology", "Cytokines" and "Mycobacterium leprae". A methodological quality assessment was carried out using the JBI checklists. Results: A total of 49 articles were included. There is a relationship of greater severity of infection associated with lower release of MHC molecules in response to PGL-1 that inhibit the promotion of resolving T lymphocytes arising from dendritic cells (DCs) stimulation. In addition, the differentiation of macrophage phenotypes dependent on the activation of PRRs can define activation and the distinct type of T helper (Th) cells involved according to severity. Activated CD8+ T cells also have distinct types at the appropriate poles of the disease, and B cells show at the most severe pole of the LL, specific induction of IgA and more Treg-type CD8+ T cells that further contribute to T cell anergy. Conclusion: Therefore, the adaptive immune system aggravates nerve damage and defines the type of leprosy, while the innate immune system is considerably more significant in the onset of nerve damage, symptomatic of the initial presentation of illness and in several critical immune responses, including inflammation and elimination of dead M. leprae. [ABSTRACT FROM AUTHOR]

Simple Summary: T regulatory cells are specialized lymphocytes that prevent excessive immune responses, yet they can suppress beneficial anti-tumor immunity when infiltrating malignant tumors. Osteopontin, a versatile protein produced by various cells, including T lymphocytes, influences both inflammation-related diseases and cancer immunity. Its role in T regulatory cells, however, remains less explored. Our study examined the impact of osteopontin deficiency on T regulatory cells. We generated mice lacking osteopontin in these cells and observed impaired immune suppression capabilities, which resulted in increased tumor-fighting activity against melanoma. These findings emphasize osteopontin's crucial role in T regulatory cell stability and functionality within the tumor microenvironment, providing valuable insights for developing new immunotherapeutic strategies. Foxp3-expressing regulatory T (Treg) cells represent the most highly immunosuppressive cell in the tumor microenvironment (TME) that halts effective anti-tumor immunity. Osteopontin (Opn), an extracellular matrix (ECM) glycophosphoprotein, plays key roles in many types of immune-related diseases and is associated with cancer aggressiveness when expressed by tumor cells. However, its role in Foxp3Treg heterogeneity, function, and stability in the TME is poorly defined. We generated mice with a Foxp3-specific deletion of Opn and assessed the ability of Opn-deficient Tregs to suppress inflammation. As these mice aged, they developed a scurfy-like syndrome characterized by aberrant and excessive activation of effector T cells. We evaluated and further confirmed the reduced suppressive capacity of Opn-deficient Tregs in an in vivo suppression assay of colitis. We also found that mice with Opn-deficient Foxp3+ Tregs have enhanced anti-tumor immunity and reduced tumor burden, associated with an unstable Treg phenotype, paralleled by reduced Foxp3 expression in tumor-infiltrating lymphocytes. Finally, we observed reduced Foxp3 and Helios expression in Opn-deficient Tregs compared to wild-type controls after in vitro activation. Our findings indicate that targeting Opn in Tregs reveals vigorous and effective ways of promoting Treg instability and dysfunction in the TME, facilitating anti-tumor immunity. [ABSTRACT FROM AUTHOR]

Toxoplasma gondii (T. gondii)‐associated polymorphic effector proteins are crucial in parasite development and regulating host anti‐T. gondii immune responses. However, the mechanism remains obscure. Here, it is shown that Toxoplasma effector dense granules 4 (GRA4) restricts host IFN‐I activation. Infection with Δgra4 mutant T. gondii strain induces stronger IFN‐I responses and poses a severe threat to host health. Mechanistically, GRA4 binds to phosphorylated TBK1 to promote TRIM27‐catalyzed K48‐ubiquitination at Lys251/Lys372 residues, which enhances its recognition by autophagy receptor p62, ultimately leading to TBK1 autophagic degradation. Furthermore, an avirulent Δgra4 strain (ME49Δompdc/gra4) is constructed for tumor immunotherapy due to its ability to enhance IFN‐I production. Earlier vaccination with ME49Δompdc/gra4 confers complete host resistance to the tumor compared with the classical ME49Δompdc treatment. Notably, ME49Δompdc/gra4 vaccination induces a specific CD64+MAR‐1+CD11b+ dendritic cell subset, thereby enhancing T cell anti‐tumor responses. Overall, these findings identify the negative role of T. gondii GRA4 in modulating host IFN‐I signaling and suggest that GRA4 can be a potential target for the development of T. gondii vaccines and tumor immunotherapy. [ABSTRACT FROM AUTHOR]

The inducible T-cell costimulator (ICOS) deficiency was first described in 2003. Autosomal re-cessive inherited ICOS deficiency is classified as combined immunodeficiency (CID) and has a wide clinical spectrum including hypogammaglobulinemia, recurrent infections, enteropathies, autoimmunity, lymphoproliferation, and malignancy. WAS/WASL Interacting Protein Family Member 1 (WIPF1) mutation causes WIP deficiency, characterized by thrombocytopenia, immu-nodeficiency, and eczema. Here, we aimed to present a patient with coexisting ICOS and WIP de-ficiency. [ABSTRACT FROM AUTHOR]

Since pregnant women were excluded from clinical trials for vaccines against SARS-CoV-2, the novel coronavirus disease 2019 (COVID-19), there is limited data on the safety and efficacy of vaccines in this population. This systematic review explored the safety and efficacy of mRNA vaccines in pregnant women. A literature search was performed using Ovid databases through November 2021 for all studies evaluated efficacy and safety of mRNA COVID-19 vaccines in pregnant women. A total of five studies including 42,782 women were included in the systematic review. Humoral immunity to COVID-19 was detected in pregnant women who received the vaccine and no differences found in spike-specific T-cell responses. Incidence of high-grade chronic villitis is higher in the unvaccinated group with adjusted odds ratio of.31 (.1-.97), P <.05. Vaccination in pregnant women resulted in 12.6% spontaneous abortions (SAB) with 92.3% occurring in the first trimester,.1% stillbirth (> 20 weeks gestation), 9.4% preterm birth (<37 weeks gestation), and 2.2% congenital abnormalities. The mRNA COVID-19 vaccines are immunogenic in pregnant women and no obvious safety concerns observed. There is no increased incidence of adverse reactions in pregnant women. Our finding supports that pregnant women should receive the vaccination at their earliest convenience regardless of trimester. [ABSTRACT FROM AUTHOR]

Aim: The aim of this paper is to clarify the critical role of GPCR signaling in T cell immunity. Methods: The G protein-coupled receptors (GPCRs) are the most common targets in current pharmaceutical industry, and represent the largest and most versatile family of cell surface communicating molecules. GPCRs can be activated by a diverse array of ligands including neurotransmitters, chemokines as well as sensory stimuli. Therefore, GPCRs are involved in many key cellular and physiological processes, such as sense of light, taste and smell, neurotransmission, metabolism, endocrine and exocrine secretion. In recent years, GPCRs have been found to play an important role in immune system. T cell is an important type of immune cell, which plays a central role in cell-mediated immunity. A variety of GPCRs and their signaling mediators (RGS proteins, GRKs and β-arrestin) have been found to express in T cells and involved T cell-mediated immunity. We will summarize the role of GPCR signaling and their regulatory molecules in T cell activation, homeostasis and function in this article. Results: GPCR signaling plays an important role in T cell activation, homeostasis and function. Conclusion: GPCR signaling is critical in regulating T cell immunity. [ABSTRACT FROM AUTHOR]

Sepsis is one of the major challenges in intensive care units, characterized by the complexity of the host immune status. To gain a deeper understanding of the pathogenesis of sepsis, it is crucial to study the phenotypic changes in immune cells and their underlying molecular mechanisms. We conducted Summary data‐based Mendelian randomization analysis by integrating genome‐wide association studies data for sepsis with expression quantitative trait locus data, revealing a significant decrease in the expression levels of 17 biomarkers in sepsis patients. Furthermore, based on single‐cell RNA sequencing data, we elucidated potential molecular mechanisms at single‐cell resolution and identified that LGALS9 inhibition in sepsis patients leads to the activation and differentiation of monocyte and T‐cell subtypes. These findings are expected to assist researchers in gaining a more in‐depth understanding of the immune dysregulation in sepsis. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are emerging as promising carriers for the delivery of therapeutic biologics. Genetic engineering represents a robust strategy for loading proteins of interest into EVs. Identification of EV‐enriched proteins facilitates protein cargo loading efficiency. Many EV‐enriched proteins are sorted into EVs via an endosomal sorting complex required for transport (ESCRT)‐dependent pathway. In parallel, viruses hijack this EV biosynthesis machinery via conserved late domain motifs to promote egress from host cells. Inspired by the similarity of biogenesis between EVs and viruses, we developed a synthetic, Late domain‐based EV scaffold protein that enables the display of a set of single chain variable fragments (scFvs) on the EV surface. We named this scaffold the Late domain‐based exosomal antibody surface display platform (LEAP). We applied the LEAP scaffold to reprogramme HEK293T cell‐derived EVs to elicit T‐cell anti‐tumor immunity by simultaneously displaying αPD‐L1 and αCD3 scFvs on the EV surface (denoted as αPD‐L1×αCD3 bispecific T‐cell engaging exosomes, BiTExos). We demonstrated that αPD‐L1×αCD3 BiTExos actively redirected T cells to bind to PD‐L1+ tumor cells, promoting T‐cell activation, proliferation and tumoricidal cytokine production. Furthermore, the αPD‐L1×αCD3 BiTExos promoted T‐cell infiltration into the tumor microenvironment to mitigate the tumor burden in vivo. Our study suggested that the LEAP scaffold may serve as a platform for EV surface display and could be applied for a broad range of EV‐based biomedical applications. [ABSTRACT FROM AUTHOR]

Simple Summary: The content as well as the status of immune cells before immunotherapy administration are indispensable for response. TAA-specific T cells have been associated with poor responses to chemotherapy. However, their role as predictive biomarkers for immunotherapy administration as well as their interplay with other immune system cells is not well understood. Our findings reveal that combined analysis of pre-existing immunity T cells of different immune parameters in treatment-naïve NSCLC patients leads to better prediction tools for immunotherapy response. T-cell-mediated anti-tumoral responses may have significant clinical relevance as a biomarker for response to immunotherapy. The value of peripheral blood pre-existing tumor antigen-specific T cells (PreI+) as a predictive immunotherapy biomarker in NSCLC patients was investigated, along with the frequency of various circulating immune cells. Fifty-two treatment-naïve, stage III/IV NSCLC patients, treated with front-line immune checkpoint inhibitors (ICI)-containing regimens were enrolled. PreI was calculated as the percentages of CD3+IFNγ+ cells after in vitro co-cultures of PBMCs with peptides against four different Tumor-Associated Antigens (TAA). Immunophenotyping of peripheral blood immune cells was performed using multicolor flow cytometry. PreI+ T cells were detected in 44% of patients. Median overall survival (OS) was significantly higher in PreI+ patients compared to PreI– patients (not reached vs. 321 days, respectively; p = 0.014). PreI+ patients had significantly higher numbers of possible exhausted CD3+CD8+PD-1+ cells and lower percentages of immunosuppressive Tregs compared to PreI− patients. Additionally, patients with PreI+ and low numbers of peripheral blood M-MDSCs had a significant survival advantage compared to the rest of the patients. Thus, combining pre-existing tumor antigen-specific immunity before initiation of ICI in NSCLC patients with selected immune-suppressive cells could identify patients who have a favorable clinical outcome when treated with ICI-containing regimens. [ABSTRACT FROM AUTHOR]

The regulatory circuits dictating CD8+ T cell responsiveness versus exhaustion during anti-tumor immunity are incompletely understood. Here we report that tumor-infiltrating antigen-specific PD-1+ TCF-1− CD8+ T cells express the immunosuppressive cytokine Fgl2. Conditional deletion of Fgl2 specifically in mouse antigen-specific CD8+ T cells prolongs CD8+ T cell persistence, suppresses phenotypic and transcriptomic signatures of T cell exhaustion, and improves control of the tumor. In a mouse model of chronic viral infection, PD-1+ CD8+ T cell-derived Fgl2 also negatively regulates virus-specific T cell responses. In humans, CD8+ T cell-derived Fgl2 is associated with poorer survival in patients with melanoma. Mechanistically, the dampened responsiveness of WT Fgl2-expressing CD8+ T cells, when compared to Fgl2-deficient CD8+ T cells, is underpinned by the cell-intrinsic interaction of Fgl2 with CD8+ T cell-expressed FcγRIIB and concomitant caspase 3/7-mediated apoptosis. Our results thus illuminate a cell-autonomous regulatory axis by which PD-1+ CD8+ T cells both express the receptor and secrete its ligand in order to mediate suppression of anti-tumor and anti-viral immunity. Mechanisms regulating CD8 T cell responsiveness are not fully understood. Here the authors show, using mouse genetic tools and human patient samples, that CD8 T-derived Fgl2, an immunosuppressive cytokine, binds autologous FcγRIIB receptor to induce CD8 T cell apoptosis and dampen anti-tumor or antivirus immunity. [ABSTRACT FROM AUTHOR]

Influenza A virus (IAV) causes significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. The antigenic drift/shift of IAV continually gives rise to new strains and subtypes, aiding IAV in circumventing previously established immunity. As a result, there has been substantial interest in developing a broadly protective IAV vaccine that induces, durable immunity against multiple IAVs. Previously, a polyanhydride nanoparticle-based vaccine or nanovaccine (IAV-nanovax) encapsulating H1N1 IAV antigens was reported, which induced pulmonary B and T cell immunity and resulted in cross-strain protection against IAV. A key feature of IAV-nanovax is its ability to easily incorporate diverse proteins/payloads, potentially increasing its ability to provide broad protection against IAV and/or other pathogens. Due to human susceptibility to both H1N1 and H3N2 IAV, several H3N2 nanovaccines were formulated herein with multiple IAV antigens to examine the "plug-and-play" nature of the polyanhydride nanovaccine platform and determine their ability to induce humoral and cellular immunity and broad-based protection similar to IAV-nanovax. The H3N2-based IAV nanovaccine formulations induced systemic and mucosal B cell responses which were associated with antigen-specific antibodies. Additionally, systemic and lung-tissue resident CD4 and CD8 T cell responses were enhanced post-vaccination. These immune responses corresponded with protection against both homologous and heterosubtypic IAV infection. Overall, these results demonstrate the plug-and-play nature of the polyanhydride nanovaccine platform and its ability to generate immunity and protection against IAV utilizing diverse antigenic payloads. [ABSTRACT FROM AUTHOR]

Activated phosphoinositide 3-kinase (PI3Kδ) Syndrome (APDS) is an inborn error of immunity (IEI) with a variable clinical presentation, characterized by infection susceptibility and immune dysregulation that may overlaps with other Primary Immune Regulatory Disorders (PIRDs). The rarity of the disease, its recent discovery, and the multiform /multifaced clinical presentation make it difficult to establish a correct diagnosis, especially at an early stage. As a result, the true prevalence of the pathology remains unknown. There is no treatment protocol for APDS, and drug therapy is primarily focused on treating symptoms. The most common therapies include immunoglobulin replacement therapy, antimicrobial prophylaxis, and immunosuppressive drugs. Hematopoietic stem cell transplantation (HSCT) has been used in some cases, but the risk-benefit balance remains unclear. With the upcoming introduction of specific medications, such as selective inhibitors for PI3Kδ, clinicians are shifting their attention towards target therapy. This review provides a comprehensive overview of APDS with a focus on diagnostic and treatments procedures available. This review may be useful in implementing strategies for a more efficient patients' management and therapeutic interventions. Main Text. [ABSTRACT FROM AUTHOR]

According to the latest evidence, the microbial metabolite Urolithin A (UA), known for its role in promoting cellular health, modulates CD8+ T cell‐mediated antitumor activity. However, the direct target protein of UA and its underlying mechanism remains unclear. Here, this research identifies ERK1/2 as the specific target crucial for UA‐mediated CD8+ T cell activation. Even at low doses, UA markedly enhances the persistence and effector functions of primary CD8+ cytotoxic T lymphocytes (CTLs) and human chimeric antigen receptor (CAR) T cells both in vitro and in vivo. Mechanistically, UA interacts directly with ERK1/2 kinases, enhancing their activation and subsequently facilitating T cell activation by engaging ULK1. The UA‐ERK1/2‐ULK1 axis promotes autophagic flux in CD8+ CTLs, enhancing cellular metabolism and maintaining reactive oxygen species (ROS) levels, as evidenced by increased oxygen consumption and extracellular acidification rates. UA‐treated CD8+ CTLs also display elevated ATP levels and enhanced spare respiratory capacity. Overall, UA activates ERK1/2, inducing autophagy and metabolic adaptation, showcasing its potential in tumor immunotherapy and interventions for diseases involving ERKs. [ABSTRACT FROM AUTHOR]

Plasma RNAemia, delayed antibody responses and inflammation predict COVID-19 outcomes, but the mechanisms underlying these immunovirological patterns are poorly understood. We profile 782 longitudinal plasma samples from 318 hospitalized patients with COVID-19. Integrated analysis using k-means reveals four patient clusters in a discovery cohort: mechanically ventilated critically-ill cases are subdivided into good prognosis and high-fatality clusters (reproduced in a validation cohort), while non-critical survivors segregate into high and low early antibody responders. Only the high-fatality cluster is enriched for transcriptomic signatures associated with COVID-19 severity, and each cluster has distinct RBD-specific antibody elicitation kinetics. Both critical and non-critical clusters with delayed antibody responses exhibit sustained IFN signatures, which negatively correlate with contemporaneous RBD-specific IgG levels and absolute SARS-CoV-2-specific B and CD4+ T cell frequencies. These data suggest that the "Interferon paradox" previously described in murine LCMV models is operative in COVID-19, with excessive IFN signaling delaying development of adaptive virus-specific immunity. The role of IFN signaling in SARS-CoV-2 infection and outcome is still debated. Here, the authors longitudinally profiled plasma samples from hospitalized patients and show that a persistent inflammatory response is linked to delayed generation of adaptive immunity and increased risk of death when coupled with severe infection. [ABSTRACT FROM AUTHOR]

Immunogenic cell death (ICD) plays a crucial role in triggering the antitumor immune response in the tumor microenvironment (TME). Recently, considerable attention has been dedicated to ferroptosis, a type of ICD that is induced by intracellular iron and has been demonstrated to change the immune desert status of the TME. However, among cancers that are characterized by an immune desert, such as prostate cancer, strategies for inducing high levels of ferroptosis remain limited. Radiated tumor cell-derived microparticles (RMPs) are radiotherapy mimetics that have been shown to activate the cGAS-STING pathway, induce tumor cell ferroptosis, and inhibit M2 macrophage polarization. RMPs can also act as carriers of agents with biocompatibility. In the present study, we designed a therapeutic system wherein the ferroptosis inducer RSL-3 was loaded into RMPs, which were tested in in vitro and in vivo prostate carcinoma models established using RM-1 cells. The apoptosis inducer CT20 peptide (CT20p) was also added to the RMPs to aggravate ferroptosis. Our results showed that RSL-3- and CT20p-loaded RMPs (RC@RMPs) led to ferroptosis and apoptosis of RM-1 cells. Moreover, CT20p had a synergistic effect on ferroptosis by promoting reactive oxygen species (ROS) production, lipid hydroperoxide production, and mitochondrial instability. RC@RMPs elevated dendritic cell (DC) expression of MHCII, CD80, and CD86 and facilitated M1 macrophage polarization. In a subcutaneously transplanted RM-1 tumor model in mice, RC@RMPs inhibited tumor growth and prolonged survival time via DC activation, macrophage reprogramming, enhancement of CD8+ T cell infiltration, and proinflammatory cytokine production in the tumor. Moreover, combination treatment with anti-PD-1 improved RM-1 tumor inhibition. This study provides a strategy for the synergistic enhancement of ferroptosis for prostate cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Background: Diabetes that only appears or is diagnosed during pregnancy is referred to as gestational diabetes mellitus (GDM). The maternal physiological immune profile is essential for a positive pregnancy outcome. However, the causal relationship between GDM and immunophenotypes is not fully defined. Methods: Based on the high-density genetic variation data at the genome-wide level, we evaluated the logical associations between 731 specific immune mediators and GDM using bidirectional Mendelian randomization (MR). The inverse variance weighted (IVW) was the main method employed for MR analysis. We performed multiple methods to verify the robustness and dependability of the MR results, and sensitivity measures were applied to rule out potential heterogeneity and horizontal pleiotropy. Results: A substantial causal association between several immune mediators and GDM was detected. After FDR testing, HLA DR++ monocyte %leukocyte and HLA DR on plasmacytoid DC were shown to increase the risk of GDM; in contrast, CD127 on CD28+ CD45RA+ CD8br and CD19 on PB/PC were shown to attenuate the effect of GDM. Moreover, the progression of GDM has been shown to decrease the maternal levels of CD39+ activated Treg AC, CD39+ activated Treg %CD4 Treg, CD39+ resting Treg AC, CD39+ resting Treg %CD4 Treg, and CD39+ CD8BR %T cell. Conclusions: Our findings support a possible causal association between GDM and various immunophenotypes, thus facilitating the provision of multiple options for preventive recognition as well as for the diagnostic and therapeutic management of GDM in clinical practice. [ABSTRACT FROM AUTHOR]

One of priority issues of the present-day healthcare system is development of new vaccines and improvement of existing ones due to decreasing immunocompetence of the population, emergence of new infections and reemergence of old ones which were previously thought to be under control. Adjuvants have proven to be integral and important components of modern vaccines, as they enhance immune response to the vaccine antigen. However, despite a lot of effort put into their development, only a small number of adjuvants are currently used in clinical practice. The aim of the study was to systematise literature data on the adjuvants’ mechanisms of action, their specific structure, composition, and stimulation effects that mediate their immunoadjuvant properties. The paper summarises data on adjuvants used as components in licensed vaccines, describes their characteristics, analyses molecular mechanisms of their action in order to establish correlation between their structure and activity, which is important for the development of more efficacious and safe adjuvants. The paper cites advanced developments aimed at enhancing stimulation effects of existing adjuvants. It concludes by stating that the key research area aimed at improving vaccination efficacy is the study of mechanisms that contribute to the development of effective protection against infectious agents, as well as analysis of how to use adjuvants to stimulate the body’s defensive mechanisms, primarily by impacting the innate immunity.

The definition of artificial immunity, realized through vaccinations, is nowadays a practice widely developed in order to eliminate cancer disease. The present paper deals with an improved version of a mathematical model recently analyzed and related to the competition between immune system cells and mammary carcinoma cells under the action of a vaccine (Triplex). The model describes in detail both the humoral and cellular response of the immune system to the tumor associate antigen and the recognition process between B cells, T cells and antigen presenting cells. The control of the tumor cells growth occurs through the definition of different vaccine protocols. The performed numerical simulations of the model are in agreement with in vivo experiments on transgenic mice. [ABSTRACT FROM AUTHOR]

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The review is devoted to specific aspects of the development of post-vaccination immunity following immunisation with different types of antiviral vaccines, as well as to ways of increasing immunogenicity of vaccines and effectiveness of preventive vaccination. Vaccines containing highly purified and recombinant antigens obtained using modern technologies have lower reactogenicity and a higher safety profile, but are less immunogenic compared to live vaccines. Effective vaccines have not been developed for many viral infections yet. Therefore, it is critical to search for ways to enhance immunogenic properties of vaccines in order to increase the efficiency of vaccination, and to develop new vaccine formulations that provide reliable protection of the body against infection. The aim of the paper was to analyse specific aspects of immune response development following immunisation with antiviral vaccines, and approaches to increasing their immunogenicity using adjuvants. It reviews different types of antiviral vaccines, as well as specific aspects of immune response development depending on the nature of a specific antigen. The paper substantiates the use of adjuvants to enhance and regulate the induced immune response. It analyses mechanisms that determine the stimulating effect of adjuvants and summarises data on the adjuvants used in the licensed vaccines for human use. The authors highlight the need for further research to increase the efficiency of vaccination and suggest that one of potential solutions is the use of adjuvants based on recombinant human cytokines.