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      CD1a-autoreactive T cells are a normal component of the human αβ T cell repertoire

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          Abstract

          CD1 activates T cells, but the functions and size of possible human T cell repertoires recognizing each of the CD1 antigen presenting molecules remain unknown. Using an experimental system that bypasses major histocompatibility complex (MHC) restriction and the requirement for defined antigens, we found that polyclonal T cells responded at higher rates to cells expressing CD1a compared to CD1b, CD1c or CD1d. Unlike invariant NKT cells, the CD1a-autoreactive repertoire contains diverse T cell receptors. Functionally, many CD1a-autoreactive T cells home to skin, where they produce interleukin 22 (IL-22) in response to CD1a on Langerhans cells. The strong and frequent responses among genetically diverse donors define CD1a-autoreactive cells as a normal part of the human T cell repertoire and CD1a as a target of T H22 cells.

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          Most cited references 47

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          Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells.

          Interleukin 22 (IL-22) is a cytokine produced by the T(H)-17 lineage of helper T cells and NK-22 subset of natural killer cells that acts on epithelial cells and keratinocytes and has been linked to skin homeostasis and inflammation. Here we characterize a population of human skin-homing memory CD4(+) T cells that expressed the chemokine receptors CCR10, CCR6 and CCR4 and produced IL-22 but neither IL-17 nor interferon-gamma (IFN-gamma). Clones isolated from this population produced IL-22 only and had low or undetectable expression of the T(H)-17 and T helper type 1 (T(H)1) transcription factors RORgammat and T-bet. The differentiation of T cells producing only IL-22 was efficiently induced in naive T cells by plasmacytoid dendritic cells in an IL-6- and tumor necrosis factor-dependent way. Our findings delineate a previously unknown subset of human CD4(+) effector T cells dedicated to skin pathophysiology.
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            Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling.

            Th subsets are defined according to their production of lineage-indicating cytokines and functions. In this study, we have identified a subset of human Th cells that infiltrates the epidermis in individuals with inflammatory skin disorders and is characterized by the secretion of IL-22 and TNF-alpha, but not IFN-gamma, IL-4, or IL-17. In analogy to the Th17 subset, cells with this cytokine profile have been named the Th22 subset. Th22 clones derived from patients with psoriasis were stable in culture and exhibited a transcriptome profile clearly separate from those of Th1, Th2, and Th17 cells; it included genes encoding proteins involved in tissue remodeling, such as FGFs, and chemokines involved in angiogenesis and fibrosis. Primary human keratinocytes exposed to Th22 supernatants expressed a transcriptome response profile that included genes involved in innate immune pathways and the induction and modulation of adaptive immunity. These proinflammatory Th22 responses were synergistically dependent on IL-22 and TNF-alpha. Furthermore, Th22 supernatants enhanced wound healing in an in vitro injury model, which was exclusively dependent on IL-22. In conclusion, the human Th22 subset may represent a separate T cell subset with a distinct identity with respect to gene expression and function, present within the epidermal layer in inflammatory skin diseases. Future strategies directed against the Th22 subset may be of value in chronic inflammatory skin disorders.
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              Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several V beta genes and an invariant TCR alpha chain

              CD4-CD8- (double negative [DN]) alpha/beta T cells are a largely uncharacterized subpopulation of unknown function. To investigate whether these cells are selected to recognize particular antigens or antigen-presenting molecules, DN alpha/beta T cells were purified from the peripheral blood of five normal donors and their T cell receptor (TCR) alpha and beta chains were examined. Random cloning of TCR alpha chains by single-sided polymerase chain reaction (PCR) amplification identified an invariant rearrangement between V alpha 24 and J alpha Q, with no N region diversity, which was expressed preferentially by DN alpha/beta T cells from all donors. Random cloning also identified a precise V alpha 7.2-J alpha (IGRJa14) rearrangement, with two variable amino acids encoded in the V-J junction, which was enriched in the DN alpha/beta T cell preparations from some, but not all, donors. Analysis of TCR beta chains by quantitative PCR amplification demonstrated that the expression of four V beta gene families, V beta 2, 8, 11, and 13, was markedly increased in these DN alpha/beta T cell preparations. The expression of particular TCRs by DN alpha/beta T cells from multiple donors indicates that these cells, or at least a subpopulation of cells with this phenotype, recognize a limited spectrum of antigens and suggests that they may use nonpolymorphic antigen-presenting molecules.
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                Author and article information

                Journal
                100941354
                21750
                Nat Immunol
                Nat. Immunol.
                Nature immunology
                1529-2908
                1529-2916
                15 June 2011
                31 October 2010
                December 2010
                07 July 2011
                : 11
                : 12
                : 1102-1109
                Affiliations
                [1 ] Division of Rheumatology, Immunology and Allergy, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
                [2 ] Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115 USA
                [3 ] Dana Farber Cancer Institute, Boston, MA 02115
                [4 ] Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
                Article
                nihpa241605
                10.1038/ni.1956
                3131223
                21037579

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                Funding
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases : NIAMS
                Award ID: R01 AR048632-10 || AR
                Funded by: National Institute of Allergy and Infectious Diseases Extramural Activities : NIAID
                Award ID: R01 AI049313-10 || AI
                Categories
                Article

                Immunology

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