Thymic egress and peripheral T cell homeostasis regulated by Rho GTPase-activating protein 30

Abstract

T cells are central to adaptive immunity, with proper thymic development and egress critical for T cell homeostasis in peripheral tissues. The molecular mechanisms governing thymic egress remain poorly understood. Here, we identify Rho GTPase-activating protein 30 (ARHGAP30), predominantly expressed in lymphoid organs and previously uncharacterized in immunity, as a key regulator of thymocyte migration and egress. Loss of ARHGAP30 leads to impaired thymic development and severe T cell lymphopenia. Notably, Arhgap30-deficient mice exhibit a reduced number of immature single-positive (SP) thymocytes but a normal number of mature SP thymocytes, indicating a blockade in thymic egress. Mechanistically, ARHGAP30 deficiency lowers GTP-bound active RAC1 independent of its GAP activity, impairing actin polarization and thymocyte motility. ARHGAP30 selectively binds and stabilizes active RAC1, preventing its proteasomal degradation via K48-linked ubiquitination. These findings establish ARHGAP30 as a critical checkpoint for thymic egress and underscore its essential role in maintaining peripheral T cell homeostasis.