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      Cellular Mediators of Inflammation: Tregs and T H17 Cells in Gastrointestinal Diseases

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          Abstract

          Human lymphocyte subpopulations were originally classified as T- and B-cells in the 70s. Later, with the development of monoclonal antibodies, it became possible to recognize, within the T-cells, functional populations: CD4 + and CD8 +. These populations were usually referred to as “helper” and “suppressor” cells, respectively. However several investigations within the CD8 cells failed to detect a true suppressor activity. Therefore the term suppressor was neglected because it generated confusion. Much later, true suppressor activity was recognized in a subpopulation of CD4 cells characterized by high levels of CD25. The novel population is usually referred to as T regulatory cells (Tregs) and it is characterized by the expression of FoxP3. The heterogeneity of CD4 cells was further expanded by the recent description of a novel subpopulation characterized by production of IL-17. These cells are generally referred to as T H17. They contribute to regulate the overall immune response together with other cytokine-producing populations. Treg and T H17 cells are related because they could derive from a common progenitor, depending on the presence of certain cytokines. The purpose of this review is to summarize recent findings of the role of these novel populations in the field of human gastroenterological disease.

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          The inhibitory cytokine IL-35 contributes to regulatory T-cell function.

          Regulatory T (T(reg)) cells are a critical sub-population of CD4+ T cells that are essential for maintaining self tolerance and preventing autoimmunity, for limiting chronic inflammatory diseases, such as asthma and inflammatory bowel disease, and for regulating homeostatic lymphocyte expansion. However, they also suppress natural immune responses to parasites and viruses as well as anti-tumour immunity induced by therapeutic vaccines. Although the manipulation of T(reg) function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. Here we demonstrate that Epstein-Barr-virus-induced gene 3 (Ebi3, which encodes IL-27beta) and interleukin-12 alpha (Il12a, which encodes IL-12alpha/p35) are highly expressed by mouse Foxp3+ (forkhead box P3) T(reg) cells but not by resting or activated effector CD4+ T (T(eff)) cells, and that an Ebi3-IL-12alpha heterodimer is constitutively secreted by T(reg) but not T(eff) cells. Both Ebi3 and Il12a messenger RNA are markedly upregulated in T(reg) cells co-cultured with T(eff) cells, thereby boosting Ebi3 and IL-12alpha production in trans. T(reg)-cell restriction of this cytokine occurs because Ebi3 is a downstream target of Foxp3, a transcription factor that is required for T(reg)-cell development and function. Ebi3-/- and Il12a-/- T(reg) cells have significantly reduced regulatory activity in vitro and fail to control homeostatic proliferation and to cure inflammatory bowel disease in vivo. Because these phenotypic characteristics are distinct from those of other IL-12 family members, this novel Ebi3-IL-12alpha heterodimeric cytokine has been designated interleukin-35 (IL-35). Ectopic expression of IL-35 confers regulatory activity on naive T cells, whereas recombinant IL-35 suppresses T-cell proliferation. Taken together, these data identify IL-35 as a novel inhibitory cytokine that may be specifically produced by T(reg) cells and is required for maximal suppressive activity.
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            Foxp3 instability leads to the generation of pathogenic memory T cells in vivo

            Regulatory T (Treg) cells play a central role in maintaining immune homeostasis. However, little is known about the stability of Treg cells in vivo. In this study, we demonstrate that a significant percentage of cells exhibited transient or unstable Foxp3 expression. These exFoxp3+ T cells express an activated-memory T cell phenotype, and produced inflammatory cytokines. Moreover, exFoxp3 cell numbers increased in inflamed tissues under autoimmune conditions. Adoptive transfer of autoreactive exFoxp3 cells led to the rapid-onset of diabetes. Finally, T cell receptor repertoire analyses suggested that exFoxp3 cells develop from both natural and adaptive Treg cells. Thus, the generation of potentially autoreactive effector T cells as a consequence of Foxp3 instability has important implications for understanding autoimmune disease pathogenesis.
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              Stimulation of CD25(+)CD4(+) regulatory T cells through GITR breaks immunological self-tolerance.

              CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gene superfamily--is predominantly expressed on CD25(+)CD4(+) T cells and on CD25(+)CD4(+)CD8(-) thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25(+)CD4(+) T cell-mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25(+)CD4(+) regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.
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                Author and article information

                Journal
                Mediators Inflamm
                MI
                Mediators of Inflammation
                Hindawi Publishing Corporation
                0962-9351
                1466-1861
                2009
                8 February 2010
                : 2009
                : 132028
                Affiliations
                Institute of Internal Medicine, Catholic University of the Sacred Heart, Rome 00168, Italy
                Author notes

                Recommended by Steven Kunkel

                Article
                10.1155/2009/132028
                2821644
                20169125
                0d7c6fb8-b994-4895-972a-1fe4b84a7ff9
                Copyright © 2009 Franco Pandolfi et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 October 2009
                : 30 November 2009
                : 8 December 2009
                Categories
                Review Article

                Immunology
                Immunology

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