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Resident memory T cells in human health and disease. Clark Rachael A Science translational medicine Resident memory T cells are non-recirculating memory T cells that persist long-term in epithelial barrier tissues, including the gastrointestinal tract, lung, skin, and reproductive tract. Resident memory T cells persist in the absence of antigens, have impressive effector functions, and provide rapid on-site immune protection against known pathogens in peripheral tissues. A fundamentally distinct gene expression program differentiates resident memory T cells from circulating T cells. Although these cells likely evolved to provide rapid immune protection against pathogens, autoreactive, aberrantly activated, and malignant resident memory cells contribute to numerous human inflammatory diseases including mycosis fungoides and psoriasis. This review will discuss both the science and medicine of resident memory T cells, exploring how these cells contribute to healthy immune function and discussing what is known about how these cells contribute to human inflammatory and autoimmune diseases. 10.1126/scitranslmed.3010641
Regulatory CD8 T cells suppress disease. Science (New York, N.Y.) A subset of CD8 T cells regulate chronic inflammation by killing pathogenic CD4 T cells. 10.1126/science.abp8243
The immunopathobiology of T cells in stress condition: a review. Cell stress & chaperones Several factors impact the immune responses such as the chemical nature of antigens, the physiologic and metabolic condition of the responsive cells, the site of antigen recognition, and neuroendocrine and pharmacological received agents. Incompatibility of host immune responses to the entrapped antigens leads to an immune pathological manner instead of an immune protection which results in the disharmony of the immune effective factors. Besides the fact that stress is one of the most common effective factors in human life, it also contributed to the protection, suppression, and pathology of the immune system. In this review article, the direct and indirect effects of the stress on the function of T cells and the contributed mechanism of action will be discussed. 10.1007/s12192-020-01105-0
T cells in myeloma. Raitakari M,Brown R D,Gibson J,Joshua D E Hematological oncology The current trend to develop immunotherapy strategies for patients with myeloma and other B cell malignancies has stimulated considerable interest in the functional state of the T cell population in these patients. Expanded clones of T cells exist in many patients with myeloma and their presence is associated with an improved survival. However, isolating T cells with tumour specificity has proven to be a difficult task and clinical immunization trials have so far failed to achieve a significant response. There is now evidence that tumour specific T cells are either tolerized or deleted following antigen presentation and that idiotype-derived, immunodominant tumour peptides may not exist in all patients. In order to develop more effective immunotherapy strategies for patients with myeloma, further studies are urgently required to identify the most appropriate tumour antigen, the nature of the interactions which take place during antigen presentation, and how to promote the cytotoxicity of autologous T cells. 10.1002/hon.704
Long live T cells. Nature immunology 10.1038/s41590-023-01581-3
Mechanical Immunoengineering of T cells for Therapeutic Applications. Lei Kewen,Kurum Armand,Tang Li Accounts of chemical research T cells, a key component in adaptive immunity, are central to many immunotherapeutic modalities aimed at treating various diseases including cancer, infectious diseases, and autoimmune disorders. The past decade has witnessed tremendous progress in immunotherapy, which aims at activation or suppression of the immune responses for disease treatments. Most strikingly, cancer immunotherapy has led to curative responses in a fraction of patients with relapsed or refractory cancers. However, extending those clinical benefits to a majority of cancer patients remains challenging. In order to improve both efficacy and safety of T cell-based immunotherapies, significant effort has been devoted to modulating biochemical signals to enhance T cell proliferation, effector functions, and longevity. Such strategies include discovery of new immune checkpoints, design of armored chimeric antigen receptor (CAR) T cells, and targeted delivery of stimulatory cytokines and so on.Despite the intense global research effort in developing novel cancer immunotherapies, a major dimension of the interactions between cancer and the immune system, its biomechanical aspect, has been largely underappreciated. Throughout their lifecycle, T cells constantly survey a multitude of organs and tissues and experience diverse biomechanical environments, such as shear force in the blood flow and a broad range of tissue stiffness. Furthermore, biomechanical properties of tissues or cells may be altered in disease and inflammation. Biomechanical cues, including both passive mechanical cues and active mechanical forces, have been shown to govern T cell development, activation, migration, differentiation, and effector functions. In other words, T cells can sense, respond to, and adapt to both passive mechanical cues and active mechanical forces.Biomechanical cues have been intensively studied at a fundamental level but are yet to be extensively incorporated in the design of immunotherapies. Nonetheless, the growing knowledge of T cell mechanobiology has formed the basis for the development of novel engineering strategies to mechanically modulate T cell immunity, a nascent field that we termed "mechanical immunoengineering". Mechanical immunoengineering exploits biomechanical cues (e.g., stiffness and external forces) to modulate T cell differentiation, proliferation, effector functions, etc., for diagnostic or therapeutic applications. It provides an additional dimension, complementary to traditional modulation of biochemical cues (e.g., antigen density and co-stimulatory signals), to tailor T cell immune responses and enhance therapeutic outcomes. For example, stiff antigen-presenting matrices have been shown to enhance T cell proliferation independently of the intensity of biochemical stimulatory signals. Current strategies of mechanical immunoengineering of T cells can be categorized into two major fields including passive mechanical cue-oriented and active force-oriented strategies. In this Account, we first present a brief overview of T cell mechanobiology. Next, we summarize recent advances in mechanical immunoengineering, discuss the roles of chemistry and material science in the development of these engineering strategies, and highlight potential therapeutic applications. Finally, we present our perspective on the future directions in mechanical immunoengineering and critical steps to translate mechanical immunoengineering strategies into therapeutic applications in the clinic. 10.1021/acs.accounts.0c00486
Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy. Cell metabolism Cancer immunotherapy is an increasingly successful strategy for the treatment of patients who have advanced or conventional therapy-resistant cancers. T cells are key mediators of tumor destruction and their specificity for tumor-expressed antigens is of paramount importance, but other T cell-intrinsic qualities, such as durability, longevity, and functionality also play important roles in determining the efficacy of immunotherapy. The cellular energetic pathways that are utilized by T cells play a key role in regulating each of these qualities. Metabolic activity, which both regulates and is regulated by cellular signaling pathways and epigenetics, also profoundly influences the trajectories of T cell differentiation and fate. In this Review, we discuss how cell metabolism influences T cell anti-tumor activity, the metabolic qualities of highly-functional T cells, and strategies to modulate metabolism for improving the immune response to tumors. 10.1016/j.cmet.2017.06.016
Editorial: Tissue Resident Memory T Cells. Mami-Chouaib Fathia,Tartour Eric Frontiers in immunology 10.3389/fimmu.2019.01018
Metabolic coordination of T cell quiescence and activation. Chapman Nicole M,Boothby Mark R,Chi Hongbo Nature reviews. Immunology Naive T cells are actively maintained in a quiescent state that promotes their survival and persistence. On antigen stimulation, T cells exit quiescence to initiate clonal expansion and effector differentiation. Initial studies focused on the immune receptors and transcriptional regulators involved in T cell quiescence and activation, but recent findings highlight cell metabolism as a crucial regulator of these processes. Here we summarize these intrinsic metabolic programmes and also describe how cell-extrinsic factors, such as nutrients and regulatory T cells, directly and indirectly balance quiescence and activation programmes in conventional T cells. We propose that immunological cues and nutrients license and tune metabolic programmes and signalling networks that communicate in a bidirectional manner to promote quiescence exit. Understanding the programmes that regulate T cell quiescence will be key for developing novel approaches to modulate protective and pathological T cell responses in human diseases. 10.1038/s41577-019-0203-y
CD4 Cytotoxic T cells - Phenotype, Function and Transcriptional Networks Controlling Their Differentiation Pathways. Immunology letters The two major subsets of peripheral T cells are classically divided into the CD4 T helper cells and the cytotoxic CD8 T cell lineage. However, the appearance of some effector CD4 T cell populations displaying cytotoxic activity, in particular during viral infections, has been observed, thus breaking the functional dichotomy of CD4 and CD8 T lymphocytes. The strong association of the appearance of CD4 cytotoxic T lymphocytes (CD4 CTLs) with viral infections suggests an important role of this subset in antiviral immunity by controlling viral replication and infection. Moreover, CD4 CTLs have been linked with anti-tumor activity and might also cause immunopathology in autoimmune diseases. This raises interest into the molecular mechanisms regulating CD4 CTL differentiation, which are poorly understood in comparison to differentiation pathways of other Th subsets. In this review, we provide a brief overview about key features of CD4 CTLs, including their role in viral infections and cancer immunity, and about the link between CD4 CTLs and immune-mediated diseases. Subsequently, we will discuss the current knowledge about transcriptional and epigenetic networks controlling CD4 CTL differentiation and highlight recent data suggesting a role for histone deacetylases in the generation of CD4 CTLs. 10.1016/j.imlet.2022.05.001
Stem cell-like memory T cells: The generation and application. Wang Yutong,Qiu Feng,Xu Yifan,Hou Xiaorui,Zhang Zhili,Huang Lei,Wang Huijun,Xing Hui,Wu Sha Journal of leukocyte biology Stem cell-like memory T cells (Tscm), are a newly defined memory T cell subset with characteristics of long life span, consistent self-renewing, rapid differentiation into effector T cells, and apoptosis resistance. These features indicate that Tscm have great therapeutic or preventive purposes, including being applied in chimeric Ag receptor-engineered T cells, TCR gene-modified T cells, and vaccines. However, the little knowledge about Tscm development restrains their applications. Strength and duration of TCR signaling, cytokines and metabolism in the T cells during activation all influence the Tscm development via regulating transcriptional factors and cell signaling pathways. Here, we summarize the molecular and cellular pathways involving Tscm differentiation, and its clinical application for cancer immunotherapy and prevention. 10.1002/JLB.5MR0321-145R
The Era of Cytotoxic CD4 T Cells. Frontiers in immunology In 1986, Mosmann and Coffman identified 2 functionally distinct subsets of activated CD4 T cells, Th1 and Th2 cells, being key in distinct T cell mediated responses. Over the past three decades, our understanding of CD4 T cell differentiation has expanded and the initial paradigm of a dichotomic CD4 T cell family has been revisited to accommodate a constantly growing number of functionally distinct CD4 T helper and regulatory subpopulations. Of note, CD4 T cells with cytotoxic functions have also been described, initially in viral infections, autoimmune disorders and more recently also in cancer settings. Here, we provide an historical overview on the discovery and characterization of cytotoxic CD4 T cells, followed by a description of their mechanisms of cytotoxicity. We emphasize the relevance of these cells in disease conditions, particularly in cancer, and we provide insights on how to exploit these cells in immunotherapy. 10.3389/fimmu.2022.867189
Cytokine Regulation and Function in T Cells. Dong Chen Annual review of immunology T lymphocytes, the major effector cells in cellular immunity, produce cytokines in immune responses to mediate inflammation and regulate other types of immune cells. Work in the last three decades has revealed significant heterogeneity in CD4 T cells, in terms of their cytokine expression, leading to the discoveries of T helper 1 (Th1), Th2, Th17, and T follicular helper (Tfh) cell subsets. These cells possess unique developmental and regulatory pathways and play distinct roles in immunity and immune-mediated pathologies. Other types of T cells, including regulatory T cells and γδ T cells, as well as innate lymphocytes, display similar features of subpopulations, which may play differential roles in immunity. Mechanisms exist to prevent cytokine production by T cells to maintain immune tolerance to self-antigens, some of which may also underscore immune exhaustion in the context of tumors. Understanding cytokine regulation and function has offered innovative treatment of many human diseases. 10.1146/annurev-immunol-061020-053702