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      The role of CD4 T cells in the pathogenesis of multiple sclerosis.

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      Journal: International review of neurobiology
      Keywords: Animals, CD4-Positive T-Lymphocytes, pathology, physiology, Cytokines, metabolism, Disease Models, Animal, Humans, Multiple Sclerosis, etiology, immunology, T-Lymphocytes, classification

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          Abstract

          T lymphocytes play a central role in the pathogenesis of multiple sclerosis (MS) (Zhang et al., 1992). Both CD4+ and CD8+ T cells have been demonstrated in MS lesions, with CD4+ T cells predominating in acute lesions and CD8+ T cells being observed more frequently in chronic lesions (Raine, 1994). Additionally, T cells are found in all four of the described histopathologic subtypes of MS (Lucchinetti et al., 2000). Activated myelin-reactive CD4+ T cells are present in the blood and cerebrospinal fluid (CSF) of MS patients; in contrast, only nonactivated myelin-reactive T cells are present in the blood of controls (Zhang et al., 1994). The success of several T-cell-targeted therapies in MS reinforces the importance of the role of the T cell in MS pathogenesis. Here, we outline basic concepts in CD4+ T-cell immunology and summarize the current understanding of the role of CD4+ T cells in the pathogenesis of MS.

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          A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.

          Heon Park, Zhaoxia Li, Xuexian O. Yang … (2005)
          Interleukin 17 (IL-17) has been linked to autoimmune diseases, although its regulation and function have remained unclear. Here we have evaluated in vitro and in vivo the requirements for the differentiation of naive CD4 T cells into effector T helper cells that produce IL-17. This process required the costimulatory molecules CD28 and ICOS but was independent of the cytokines and transcription factors required for T helper type 1 or type 2 differentiation. Furthermore, both IL-4 and interferon-gamma negatively regulated T helper cell production of IL-17 in the effector phase. In vivo, antibody to IL-17 inhibited chemokine expression in the brain during experimental autoimmune encephalomyelitis, whereas overexpression of IL-17 in lung epithelium caused chemokine production and leukocyte infiltration. Thus, IL-17 expression characterizes a unique T helper lineage that regulates tissue inflammation.
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            TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells.

            Marc Veldhoen, Richard J Hocking, Christopher Atkins … (2006)
            We describe de novo generation of IL-17-producing T cells from naive CD4 T cells, induced in cocultures of naive CD4 T cells and naturally occurring CD4+ CD25+ T cells (Treg) in the presence of TLR3, TLR4, or TLR9 stimuli. Treg can be substituted by TGFbeta1, which, together with the proinflammatory cytokine IL-6, supports the differentiation of IL-17-producing T cells, a process that is amplified by IL-1beta and TNFalpha. We could not detect a role for IL-23 in the differentiation of IL-17-producing T cells but confirmed its importance for their survival and expansion. Transcription factors GATA-3 and T-bet, as well as its target Hlx, are absent in IL-17-producing T cells, and they do not express the negative regulator for TGFbeta signaling, Smad7. Our data indicate that, in the presence of IL-6, TGFbeta1 subverts Th1 and Th2 differentiation for the generation of IL-17-producing T cells.
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              Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.

              Laurent Monney, Catherine Sabatos, Jason L Gaglia … (2002)
              Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.
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                Author and article information

                Journal
                PubMed ID:: 17531837
                DOI:: 10.1016/S0074-7742(07)79003-7

                ScienceOpen disciplines: Chemistry
                Keywords: Animals,CD4-Positive T-Lymphocytes,pathology,physiology,Cytokines,metabolism,Disease Models, Animal,Humans,Multiple Sclerosis,etiology,immunology,T-Lymphocytes,classification
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                ScienceOpen disciplines: Chemistry
                Keywords: Animals, CD4-Positive T-Lymphocytes, pathology, physiology, Cytokines, metabolism, Disease Models, Animal, Humans, Multiple Sclerosis, etiology, immunology, T-Lymphocytes, classification

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