MTORC2 controls T-cell receptor processing and surface expression during thymocyte development (115.18)

Abstract

Abstract An efficient immune response relies on the presence of T-cells expressing a functional T-cell receptor (TCR). While the mechanisms generating TCR diversity for antigenic recognition are well defined, what controls its surface expression is less known. The mammalian target of rapamycin (mTOR) forms two structurally and functionally distinct protein complexes, mTOR complex 1 (mTORC1) and mTORC2. While mTORCs were found to regulate T lymphocyte activation and lineage commitment, their role in early thymocyte development remains to be defined. Here we found that mTORC2 modulates T-cell ontogeny and activation by controlling the quantity of TCR that reaches the cell surface of developing thymocytes as well as transformed T-cells. Deletion of the mTORC2 component rictor at early stages of T cell ontogeny (DN2 and onward) led to aberrant maturation and increased proteasomal degradation of nascent TCR polypeptides. Consequently, the levels of TCR as well as other receptors, including CD4, CD8 and CD147 were significantly attenuated on the surface of rictor-deficient thymocytes. Since CD147 was also defectively glycosylated and expressed in SIN1-deficient fibroblasts, our findings suggest that mTORC2 is involved in the co/post-translational processing of membrane receptors. Thus, we uncover a novel function for mTORC2 that provides rationale to target this complex in disorders caused by deregulated expression of surface receptors.