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      Distinct Roles of Cdc42 in Thymopoiesis and Effector and Memory T Cell Differentiation

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          Abstract

          Cdc42 of the Rho GTPase family has been implicated in cell actin organization, proliferation, survival, and migration but its physiological role is likely cell-type specific. By a T cell-specific deletion of Cdc42 in mouse, we have recently shown that Cdc42 maintains naïve T cell homeostasis through promoting cell survival and suppressing T cell activation. Here we have further investigated the involvement of Cdc42 in multiple stages of T cell differentiation. We found that in Cdc42 −/− thymus, positive selection of CD4 +CD8 + double-positive thymocytes was defective, CD4 + and CD8 + single-positive thymocytes were impaired in migration and showed an increase in cell apoptosis triggered by anti-CD3/-CD28 antibodies, and thymocytes were hyporesponsive to anti-CD3/-CD28-induced cell proliferation and hyperresponsive to anti-CD3/-CD28-stimulated MAP kinase activation. At the periphery, Cdc42-deficient naive T cells displayed an impaired actin polymerization and TCR clustering during the formation of mature immunological synapse, and showed an enhanced differentiation to Th1 and CD8 + effector and memory cells in vitro and in vivo. Finally, Cdc42 −/− mice exhibited exacerbated liver damage in an induced autoimmune disease model. Collectively, these data establish that Cdc42 is critically involved in thymopoiesis and plays a restrictive role in effector and memory T cell differentiation and autoimmunity.

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          Most cited references41

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          Immunological decision-making: how does the immune system decide to mount a helper T-cell response?

          Aberrant T-cell responses underpin a range of diseases, including asthma and allergy and autoimmune diseases. Pivotal immune elements of these diseases are the development of antigen-specific effector T-helper type 2 (Th2) cells, Th1 cells, or the recently defined Th17 cells that are associated with the clinical features and disease progression. In order to identify crucial processes in the pathogenesis of these diseases it is critical to understand how the development of these T cells occurs. The phenotype of a polarized T-cell that differentiates from a naïve precursor is determined by the complex interaction of antigen-presenting cells with naïve T cells and involves a multitude of factors, including the dominant cytokine environment, costimulatory molecules, type and load of antigen presented and a plethora of signaling cascades. The decision to take the immune response in a certain direction is not made by one signal alone, instead many different elements act synergistically, antagonistically and through positive feedback loops to activate a Th1, Th2, or Th17 immune response. The elucidation of the mechanisms of selection of T-cell phenotype will facilitate the development of therapeutic strategies to intervene in the development of deleterious T-cell responses. This review will focus on the pathways and key factors responsible for the differentiation of the various subsets of effector CD4 T cells. We will primarily discuss what is known of the Th1 and Th2 differentiation pathways, while also reviewing the emerging research on Th17 differentiation.
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            T cell receptor signaling precedes immunological synapse formation.

            The area of contact between a T cell and an antigen-presenting cell (APC) is known as the immunological synapse. Although its exact function is unknown, one model suggests that it allows for T cell receptor (TCR) clustering and for sustained signaling in T cells for many hours. Here we demonstrate that TCR-mediated tyrosine kinase signaling in naïve T cells occurred primarily at the periphery of the synapse and was largely abated before mature immunological synapses had formed. These data suggest that many hours of TCR signaling are not required for T cell activation. These observations challenge current ideas about the role of immunological synapses in T cell activation.
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              Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice.

              The p42 and p44 mitogen-activated protein kinases (MAPKs), also called Erk2 and Erk1, respectively, have been implicated in proliferation as well as in differentiation programs. The specific role of the p44 MAPK isoform in the whole animal was evaluated by generation of p44 MAPK-deficient mice by homologous recombination in embryonic stem cells. The p44 MAPK-/- mice were viable, fertile, and of normal size. Thus, p44 MAPK is apparently dispensable and p42 MAPK (Erk2) may compensate for its loss. However, in p44 MAPK-/- mice, thymocyte maturation beyond the CD4+CD8+ stage was reduced by half, with a similar diminution in the thymocyte subpopulation expressing high levels of T cell receptor (CD3high). In p44 MAPK-/- thymocytes, proliferation in response to activation with a monoclonal antibody to the T cell receptor in the presence of phorbol myristate acetate was severely reduced even though activation of p42 MAPK was more sustained in these cells. The p44 MAPK apparently has a specific role in thymocyte development.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2011
                24 March 2011
                : 6
                : 3
                : e18002
                Affiliations
                [1 ]Division of Experimental Hematology and Cancer Biology, Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America
                [2 ]Division of Immunobiology, Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America
                [3 ]Microbiology Institute-Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen und Friedrich-Alexander Universität Erlangen-Nürnberg, Erlangen, Germany
                [4 ]Division of Pathology, Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America
                University of Georgia, United States of America
                Author notes

                Conceived and designed the experiments: FG PT J. Mattner DH YZ. Performed the experiments: FG SZ PT J. Mattner JP AS J. Muo. Analyzed the data: FG J. Mattner J. Muo DH YZ. Contributed reagents/materials/analysis tools: FG J. Mattner J. Muo MW HLG DH YZ. Wrote the paper: FG DH YZ.

                Article
                PONE-D-11-00870
                10.1371/journal.pone.0018002
                3063799
                21455314
                501c4c70-e5b0-425c-869b-aba0b44a7a71
                Guo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 4 January 2011
                : 17 February 2011
                Page count
                Pages: 12
                Categories
                Research Article
                Biology
                Immunology
                Immune Cells
                T Cells
                Immunity
                Adaptive Immunity
                Immune Activation
                Immune Response
                Molecular Cell Biology
                Cell Death
                Cell Growth

                Uncategorized
                Uncategorized

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