TNFAIP8 polarity proteins mediate T cell development by propagating lipid second messenger signaling in thymocytes.

T lymphocytes are primarily generated in the thymus through a complex process of positive and negative selections. The molecular mechanisms underlying this process are not fully understood. Here, we report that TNFAIP8 (TNF-α-induced protein 8-like) family of polarity proteins mediates T cell development by propagating phosphoinositide signaling in the thymus. Genetic deletion of hematopoietic members of the TNFAIP8 family resulted in dramatic reductions in thymus size, cellularity, and corticomedullary differentiation. Total thymocyte counts in Tnfaip8-deficient mice were reduced by more than 50%, which was associated with marked reductions in T cell numbers in blood and in secondary lymphoid organs, as compared to wild-type mice. Bone marrow chimeric experiments revealed that the thymic developmental defect was hematopoietic cell-intrinsic. TNFAIP8 proteins controlled double negative (DN) thymocyte proliferation and metabolism during positive selection by promoting PI3K-AKT/mTOR signaling through phosphoinositide second messengers. Pharmaceutical activation of AKT partially rectified the thymic developmental defect of Tnfaip8-deficient mice. Thus, TNFAIP8 polarity proteins are essential for thymic development of T lymphocytes, and genetic or pharmaceutical manipulation of the TNFAIP8 pathway may be useful for controlling T lymphocyte-mediated immunity.