Overexpression of suppressor of cytokine signaling-4 impairs T cell development and homeostasis (LYM7P.723)

Abstract

Abstract Suppressor Of Cytokine Signaling molecules (SOCS) are key players in regulating cytokine signaling. SOCS inhibits cytokine-induced JAK/STAT signaling by directly binding to JAK or by competing with cytokine receptor downstream signaling molecules. So far, eight SOCS family members have been identified, but only a few are known to play roles in the immune system. Here we identified SOCS4 as a SOCS family member whose expression is regulated during thymocyte development, with high mRNA and protein expression at the CD4, CD8 double positive stage and downregulation upon positive selection. To assess the role of SOCS4 during thymocyte development, we generated transgenic mice overexpressing a murine SOCS4 cDNA under the control of a human CD2 mini-cassette. Interestingly, SOCS4 overexpression resulted in reduced thymocyte numbers but did not affect CD4/CD8 lineage choice. Surprisingly, SOCS4 overexpression did not inhibit cytokine signaling. Instead, we found that SOCS4 transgenic T cells showed decreased ability to upregulate CD69 and CD5 following TCR stimulation. Moreover, we found that SOCS4 overexpression impaired positive selection in the thymus and interfered with T cell homeostasis in HY TCR transgenic mice. These results suggest a new role for SOCS4 in T cell development and homeostasis, independent of cytokine signaling.