Research ArticleImmunology

Regulation of thymocyte trafficking by Tagap, a GAP domain protein linked to human autoimmunity

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Sci. Signal.  12 Jun 2018:
Vol. 11, Issue 534, eaan8799
DOI: 10.1126/scisignal.aan8799

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Letting thymocytes go

During the process of T cell development, thymocytes must travel from the cortex of the thymus to the medulla, where any potentially autoreactive cells are removed by negative selection. This translocation is mediated by interactions between sema3E, which is secreted from the medulla, and its receptor plexin-D1, which is present on thymocytes in the cortex. Duke-Cohan et al. found that mouse thymocytes lacking the GTPase-activating protein Tagap had defective sema3E/plexin-D1 signaling and thus failed to detach from the cortex. Given that single-nucleotide polymorphisms in the gene encoding TAGAP are associated with autoimmune disorders, these data suggest that Tagap facilitates the trafficking required for the efficient negative selection of autoreactive cells.

Abstract

Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP, which encodes TAGAP, a guanosine triphosphatase (GTPase)–activating protein. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes’ adhesion to the cortex through their β1-containing integrins. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection. Tagap physically interacted with the cytoplasmic domain of plexin-D1 and directly stimulated the activity and signaling of the GTPase RhoA. In addition, Tagap indirectly mediated the activation of Cdc42 in response to the binding of sema3E to plexin-D1. Both RhoA and Cdc42 are key mediators of cytoskeletal and integrin dynamics in thymocytes. Knockdown of Tagap in mice suppressed the sema3E- and plexin-D1–mediated release of thymocytes that adhered within the cortex through β1-containing integrins. This suppression led to the impaired translocation of thymocytes from the cortex to the medulla and resulted in the formation of ectopic medullary structures within the thymic cortex. Our results suggest that TAGAP variation modulates the risk of autoimmunity by altering thymocyte migration during thymic selection.

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