Soluble γc cytokine receptor suppresses IL-15 signaling and impairs iNKT cell development in the thymus

Abstract

The soluble gamma c protein (s gamma c) is a naturally occurring splice isoform of the gamma c cytokine receptor that is produced by activated T cells and inhibits gamma c cytokine signaling. Here we show that s gamma c expression is also highly upregulated in immature CD4(+)CD8(+) thymocytes but then downregulated in mature thymocytes. These results indicate a developmentally controlled mechanism for s gamma c expression and suggest a potential role for s gamma c in regulating T cell development in the thymus. Indeed, s gamma c overexpression resulted in significantly reduced thymocyte numbers and diminished expansion of immature thymocytes, concordant to its role in suppressing signaling by IL-7, a critical gamma c cytokine in early thymopoiesis. Notably, s gamma c overexpression also impaired generation of iNKT cells, resulting in reduced iNKT cell percentages and numbers in the thymus. iNKT cell development requires IL-15, and we found that s gamma c interfered with IL-15 signaling to suppress iNKT cell generation in the thymus. Thus, s gamma c represents a new mechanism to control cytokine availability during T cell development that constrains mature T cell production and specifically iNKT cell generation in the thymus.