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Nat Immunol. 2017 Apr;18(4):433-441. doi: 10.1038/ni.3692. Epub 2017 Feb 27.

THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1.

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Section on Hematopoiesis and Lymphocyte Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.
Centre de Physiopathologie de Toulouse Purpan, Toulouse, France.
Institut National de la Santé et de la Recherche Médicale, U1043, Centre National de la Recherche Scientifique, U5282, and Université de Toulouse, Université Paul Sabatier, Toulouse, France.
National Library of Medicine, National Institutes of Health, Bethesda, Maryland, USA.


THEMIS, a T cell-specific protein with high expression in CD4+CD8+ thymocytes, has a crucial role in positive selection and T cell development. THEMIS lacks defined catalytic domains but contains two tandem repeats of a distinctive module of unknown function (CABIT). Here we found that THEMIS directly regulated the catalytic activity of the tyrosine phosphatase SHP-1. This action was mediated by the CABIT modules, which bound to the phosphatase domain of SHP-1 and promoted or stabilized oxidation of SHP-1's catalytic cysteine residue, which inhibited the tyrosine-phosphatase activity of SHP-1. Deletion of SHP-1 alleviated the developmental block in Themis-/- thymocytes. Thus, THEMIS facilitates thymocyte positive selection by enhancing the T cell antigen receptor signaling response to low-affinity ligands.

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