CXCR4 acts as a costimulator during thymic Β-selection

Passage through the Β-selection developmental checkpoint requires productive rearrangement of segments of the T cell antigen receptor-Β gene (Tcrb) and formation of a pre-TCR on the surface of CD⁴ CD ⁸ thymocytes. How other receptors influence ΒΒ-selection is less well understood. Here we define a new role for the chemokine receptor CXCR4 during T cell development. CXCR4 functionally associated with the pre-TCR and influenced Β-selection by regulating the steady-state localization of immature thymocytes in thymic subregions, by facilitating optimal pre-TCR-induced survival signals, and by promoting thymocyte proliferation. We also characterize functionally relevant signaling molecules downstream of CXCR4 and the pre-TCR in thymocytes. Our data designate CXCR4 as a costimulator of the pre-TCR during Β-selection.