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Immunity Feb 2018Throughout life, T cells coordinate multiple aspects of adaptive immunity, including responses to pathogens, allergens, and tumors. In mouse models, the role of... (Review)
Review
Throughout life, T cells coordinate multiple aspects of adaptive immunity, including responses to pathogens, allergens, and tumors. In mouse models, the role of T cells is studied in the context of a specific type of pathogen, antigen, or disease condition over a limited time frame, whereas in humans, T cells control multiple insults simultaneously throughout the body and maintain immune homeostasis over decades. In this review, we discuss how human T cells develop and provide essential immune protection at different life stages and highlight tissue localization and subset delineation as key determinants of the T cell functional role in immune responses. We also discuss how anatomic compartments undergo distinct age-associated changes in T cell subset composition and function over a lifetime. It is important to consider age and tissue influences on human T cells when developing targeted strategies to modulate T cell-mediated immunity in vaccines and immunotherapies.
Topics: Adaptive Immunity; Animals; Humans; Immunologic Memory; Lymphopoiesis; T-Lymphocyte Subsets; T-Lymphocytes; T-Lymphocytes, Regulatory; Tissue Distribution
PubMed: 29466753
DOI: 10.1016/j.immuni.2018.01.007 -
Annual Review of Immunology Apr 2018Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development,... (Review)
Review
Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.
Topics: Animals; Biomarkers; Cell Differentiation; Energy Metabolism; Humans; Immunity; Immunologic Memory; Immunotherapy; Lymphocyte Activation; Mitochondria; Receptors, Antigen, T-Cell; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 29677474
DOI: 10.1146/annurev-immunol-042617-053019 -
Frontiers in Immunology 2022In 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.... (Review)
Review
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.
Topics: CD4-Positive T-Lymphocytes; Lymphocyte Activation; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; Th2 Cells
PubMed: 35572552
DOI: 10.3389/fimmu.2022.867189 -
Blood Sep 2008In 1986, Mosmann and Coffman identified 2 subsets of activated CD4 T cells, Th1 and Th2 cells, which differed from each other in their pattern of cytokine production and... (Review)
Review
In 1986, Mosmann and Coffman identified 2 subsets of activated CD4 T cells, Th1 and Th2 cells, which differed from each other in their pattern of cytokine production and their functions. Our understanding of the importance of the distinct differentiated forms of CD4 T cells and of the mechanisms through which they achieve their differentiated state has greatly expanded over the past 2 decades. Today at least 4 distinct CD4 T-cell subsets have been shown to exist, Th1, Th2, Th17, and iTreg cells. Here we summarize much of what is known about the 4 subsets, including the history of their discovery, their unique cytokine products and related functions, their distinctive expression of cell surface receptors and their characteristic transcription factors, the regulation of their fate determination, and the consequences of their abnormal activation.
Topics: Animals; CD4-Positive T-Lymphocytes; Cell Differentiation; Cytokines; Epigenesis, Genetic; History, 20th Century; History, 21st Century; Humans; Mice; Models, Immunological; Mutation; Polymorphism, Genetic; Receptors, Chemokine; Receptors, Cytokine; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Th1 Cells; Th2 Cells; Transcription Factors
PubMed: 18725574
DOI: 10.1182/blood-2008-05-078154 -
Seminars in Immunopathology May 2019Forming the outer body barrier, our skin is permanently exposed to pathogens and environmental hazards. Therefore, skin diseases are among the most common disorders. In... (Review)
Review
Forming the outer body barrier, our skin is permanently exposed to pathogens and environmental hazards. Therefore, skin diseases are among the most common disorders. In many of them, the immune system plays a crucial pathogenetic role. For didactic and therapeutic reasons, classification of such immune-mediated skin diseases according to the underlying dominant immune mechanism rather than to their clinical manifestation appears to be reasonable. Immune-mediated skin diseases may be mediated mainly by T cells, by the humoral immune system, or by uncontrolled unspecific inflammation. According to the involved T cell subpopulation, T cell-mediated diseases may be further subdivided into T1 cell-dominated (e.g., vitiligo), T2 cell-dominated (e.g., acute atopic dermatitis), T17/T22 cell-dominated (e.g., psoriasis), and Treg cell-dominated (e.g., melanoma) responses. Moreover, T cell-dependent and -independent responses may occur simultaneously in selected diseases (e.g., hidradenitis suppurativa). The effector mechanisms of the respective T cell subpopulations determine the molecular changes in the local tissue cells, leading to specific microscopic and macroscopic skin alterations. In this article, we show how the increasing knowledge of the T cell biology has been comprehensively translated into the pathogenetic understanding of respective model skin diseases and, based thereon, has revolutionized their daily clinical management.
Topics: Animals; Anti-Inflammatory Agents; Biomarkers; Combined Modality Therapy; Cytokines; Dermatitis; Disease Susceptibility; Humans; Immunotherapy; Skin; T-Lymphocyte Subsets; T-Lymphocytes
PubMed: 31028434
DOI: 10.1007/s00281-019-00742-7 -
Archivum Immunologiae Et Therapiae... Dec 2014It is well established that CD8(+) T cells constitute an important branch of adaptive immunity contributing to clearance of intracellular pathogens and providing... (Review)
Review
It is well established that CD8(+) T cells constitute an important branch of adaptive immunity contributing to clearance of intracellular pathogens and providing long-term protection. These functions are mostly fulfilled by the best characterized subpopulation of CD8(+) T cells, the cytotoxic T lymphocytes (also called Tc1 cells), owing to their ability to kill infected cells and to secrete cytokines such as interferon-γ and tumor necrosis factor-α. However, there is growing evidence for alternative CD8(+) T cell fates influencing CD4(+) T-cell-mediated responses in the context of allergy, autoimmunity and infections. Thus, like subpopulations of CD4(+) T cells, also CD8(+) T cells under particular conditions acquire the expression of interleukin (IL)-4, IL-5, IL-9, IL-13, IL-17 or suppressive activity and thereby influence immune responses. The process of CD8(+) T-cell differentiation is dictated by antigen strength, co-stimulatory molecules and cytokines. These environmental cues induce transcription factors further specifying CD8(+) T-cell decision into Tc1, Tc2, Tc9, Tc17 or CD8(+) T regulatory fate. Here, we discuss our current understanding about functional diversity of effector CD8(+) T cells and contribution of transcription factors to this process.
Topics: Adaptive Immunity; Animals; CD8-Positive T-Lymphocytes; Cell Differentiation; Cytokines; Gene Expression Regulation; Humans; Immunologic Memory; Lymphocyte Activation; Mice; Signal Transduction; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Regulatory
PubMed: 24879097
DOI: 10.1007/s00005-014-0293-y -
Science (New York, N.Y.) Feb 2010CD4+ T cells are critical for host defense but are also major drivers of immune-mediated disease. These T cells specialize to become distinct subsets and produce... (Review)
Review
CD4+ T cells are critical for host defense but are also major drivers of immune-mediated disease. These T cells specialize to become distinct subsets and produce restricted patterns of cytokines, which are tailored to combat various microbial pathogens. Although classically viewed as distinct lineages, recent work calls into question whether helper CD4+ T cell subsets are more appropriately viewed as terminally differentiated cells or works in progress. Herein, we review recent advances that pertain to this topic and the mechanisms that contribute to helper CD4+ T cell commitment and plasticity. The therapeutic implications of these new findings are also considered.
Topics: Animals; Cell Differentiation; Cell Lineage; Cytokines; Gene Expression Regulation; Humans; Models, Biological; T-Lymphocyte Subsets; T-Lymphocytes, Helper-Inducer
PubMed: 20185720
DOI: 10.1126/science.1178334 -
The Journal of Investigative Dermatology Apr 2023OX40 is an important costimulatory molecule for T-cell expansion and survival. Because OX40 is expressed on most T-cell subsets, it is an attractive therapeutic target... (Review)
Review
OX40 is an important costimulatory molecule for T-cell expansion and survival. Because OX40 is expressed on most T-cell subsets, it is an attractive therapeutic target for a variety of T-cell‒mediated diseases. Clinical trials are already underway for some skin inflammatory diseases. In this review, we present various observations that improve our understanding of how OX40-targeted therapy can be applied for skin inflammatory diseases, such as atopic dermatitis and psoriasis, T helper (Th)2- and Th17-mediated diseases, respectively. The important OX40/OX40L-mediated interaction between T cells and other immune cells is also discussed in terms of skin autoimmune diseases, such as alopecia areata and pemphigus. Regulatory T cells (Tregs) highly express OX40, and the skin harbors a large Treg population; thus, understanding how OX40-targeted treatment acts on Tregs is vital for the development of therapeutic strategies for various skin diseases.
Topics: Humans; Autoimmune Diseases; Dermatitis, Atopic; Receptors, OX40; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; T-Lymphocytes
PubMed: 36842860
DOI: 10.1016/j.jid.2022.11.009 -
Nature Communications Mar 2021Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we...
Crohn's disease (CD) is a chronic transmural inflammation of intestinal segments caused by dysregulated interaction between microbiome and gut immune system. Here, we profile, via multiple single-cell technologies, T cells purified from the intestinal epithelium and lamina propria (LP) from terminal ileum resections of adult severe CD cases. We find that intraepithelial lymphocytes (IEL) contain several unique T cell subsets, including NKp30γδT cells expressing RORγt and producing IL-26 upon NKp30 engagement. Further analyses comparing tissues from non-inflamed and inflamed regions of patients with CD versus healthy controls show increased activated T17 but decreased CD8T, γδT, T and Treg cells in inflamed tissues. Similar analyses of LP find increased CD8, as well as reduced CD4T cells with an elevated T17 over Treg/T ratio. Our analyses of CD tissues thus suggest a potential link, pending additional validations, between transmural inflammation, reduced IEL γδT cells and altered spatial distribution of IEL and LP T cell subsets.
Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cells, Cultured; Crohn Disease; Gene Expression Profiling; Humans; Intraepithelial Lymphocytes; Lymphocyte Count; Single-Cell Analysis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory; Th17 Cells
PubMed: 33771991
DOI: 10.1038/s41467-021-22164-6 -
Immunity Mar 2023In the past few decades, a number of transformative discoveries have been made regarding memory CD8 T cell biology; meanwhile, the CD4 T cell field has lagged behind... (Review)
Review
In the past few decades, a number of transformative discoveries have been made regarding memory CD8 T cell biology; meanwhile, the CD4 T cell field has lagged behind this progress. This perspective focuses on CD4 helper T (Th) cell subset specification and memory cell formation. Here, we argue that the sheer number of Th effector and memory cell subsets and a focus on their differences have been a barrier to a general model of CD4 memory T cell formation that applies to all immune responses. We highlight a bifurcation model that relies on an IL-2 signal-dependent switch as an explanation for the balanced production of diverse Th memory cells that participate in cell-mediated or humoral immunity in most contexts.
Topics: T-Lymphocyte Subsets; CD4-Positive T-Lymphocytes; T-Lymphocytes, Helper-Inducer; CD8-Positive T-Lymphocytes; Immunologic Memory
PubMed: 36921574
DOI: 10.1016/j.immuni.2023.02.010