RORt limits the amount of the cytokine receptor c through the prosurvival factor Bcl-xL in developing thymocytes

Abstract

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