RORγt limits the amount of the cytokine receptor γc through the prosurvival factor Bcl-xL in developing thymocytes

Abstract

The cytokine receptor subunit gamma c provides critical signals for T cell survival and differentiation. We investigated the molecular mechanism that controls the cell surface abundance of gamma c during T cell development in the thymus. We found that the amount of gamma c was low on CD4(+)CD8(+) double-positive (DP) thymocytes before their positive selection to become mature T cells. The transcription factor ROR gamma t was abundant in immature DP thymocytes, and its loss resulted in an increase in the abundance of surface gamma c, specifically on preselection DP cells. Rather than directly repressing expression of the gene encoding gamma c, ROR gamma t acted through the antiapoptotic protein Bcl-x(L) to reduce the abundance of surface gamma c, which resulted in decreased cytokine signaling and was associated with inhibition of cell metabolism and mitochondrial biogenesis. Accordingly, overexpression of Bcl-x(L) in ROR gamma t-deficient thymocytes restored the amount of surface gamma c to that present on normal preselection DP cells. Together, these data highlight a previously unappreciated role for ROR gamma t and Bcl-x(L) in limiting gamma c abundance at the cell surface and reveal a signaling circuit in which survival factors control cytokine signaling by limiting the abundance and surface distribution of a receptor subunit shared by several cytokines.