The MRTFs are required for thymocyte trafficking and Treg-mediated immune tolerance

The MRTFs (myocardin-related transcription factors) are essential for effective cytoskeletal function during differentiation and development. To investigate the role played by the MRTFs in T cell development and function we inactivated Mrtfb in Mrtfa-null mice at the DN2 stage (MrtfabKOT animals). Positive selection, and development of MrtfabKOT regulatory (Treg), {gamma}{delta}, and NK T cells proceeded normally. Thymic egress was impaired, however, with mature T cells accumulating at the cortico-medullary junction, and in vitro MrtfabKOT thymocytes exhibited impaired cytoskeletal responses to S1P and migratory cytokines. MrtfabKOT mice were lymphopenic, with defective homeostatic proliferation and T cell homing to peripheral lymphoid organs. Although thymocyte negative selection was unaffected, MrtfabKOT animals develop autoimmune phenotypes in lacrimal gland and intestinal mucosa. Using the experimental colitis model, we show that these phenotypes reflect functional deficits in MrtfabKOT Treg cells. Our findings show that MRTF-SRF signalling plays an unanticipated role in thymocyte egress and immune tolerance, and reveal a role of the MRTFs in Treg function.