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.

多种自身免疫病理与人类基因TAGAP的单核苷酸多态性有关，该基因编码TAGAP，鸟苷三磷酸酶（GTPase）活化蛋白。我们在小鼠中显示该TAGAP介导的通过它们的β由sema3E /丛蛋白-D1配体-受体复合物的信号衰减胸腺粘附于皮质₁含整联蛋白。通过促进胸腺皮质内的胸腺细胞脱离，Tagap介导的信号转导使它们易位至延髓，这是持续进行胸腺选择所必需的。Tagap与plexin-D1的胞质域发生物理相互作用，并直接刺激GTPase RhoA的活性和信号传导。此外，Tagap响应sema3E与plexin-D1的结合而间接介导了Cdc42的激活。RhoA和Cdc42都是胸腺细胞中细胞骨架和整联蛋白动力学的关键介体。在小鼠中敲除TAGAP的抑制胸腺细胞的sema3E-和丛蛋白-D1-介导释放，通过β附着内皮层₁含整联蛋白。这种抑制导致胸腺细胞从皮质向髓质的移位受损，并导致胸腺皮质内异位髓质结构的形成。我们的结果表明，TAGAP变异通过在胸腺选择过程中改变胸腺细胞迁移来调节自身免疫的风险。