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

See allHide authors and affiliations

Science Signaling  28 Aug 2018:
Vol. 11, Issue 545, eaam8939
DOI: 10.1126/scisignal.aam8939

Limiting cytokine signals

Thymocyte development in the thymus depends on signals transduced by the T cell receptor (TCR) and cytokine receptors, including those that share the common γ chain (γc). Prior to positive selection, CD4+CD8+ double-positive (DP) thymocytes reduce their cell surface abundance of γc so that their fate is determined by TCR signaling. Ligons et al. found that loss of the transcriptional regulator RORγt in mouse DP thymocytes was associated with increased γc surface abundance. Enforced expression of RORγt reduced the abundance of γc and normalized thymocyte development. RORγt had no effect on expression of the gene encoding γc. Instead, the RORγt effector molecule Bcl-xL was required to reduce γc abundance, highlighting an unappreciated role for survival factors in modulating cytokine signaling.


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

View Full Text

Stay Connected to Science Signaling