IMMUNOBIOLOGY Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8 thymocytes

SOCS1 / mice die prematurely of increased interferon(IFN ) signaling with severe thymic atrophy and accelerated maturation of T cells. However, it was unclear whether the thymic defects were caused by SOCS1 deficiency or by increased IFN signaling. Using SOCS1 / IFN / mice, we show in this study that SOCS1 deficiency skews thymocyte development toward CD8 lineage independently of IFN . Fetal thymic organ cultures and intrathymic transfer of CD4 CD8 precursors into Rag1 / mice show that the lineage skewing in SOCS1 / mice is a T-cell autonomous defect. Interestingly, SOCS1 is not required for attenuating interleukin-7 (IL-7) signaling at the CD4 CD8 stage but is essential for regulating IL-15 and IL-2 signaling in CD8 thymocytes. IL-15 selectively stimulates SOCS1 / CD8 thymocytes, inducing sustained signal transducer and activator of transcription 5 (STAT5) phosphorylation and massive proliferation. IL-15 also strongly upregulates Bcl-xL and CD44 in CD8 thymocytes lacking SOCS1. The SOCS1 gene is induced in CD4 thymocytes by c cytokines, whereas CD8 thymocytes constitutively express SOCS1 mRNA even in the absence of cytokine stimulation. Because many different cell types express IL-15, our results strongly suggest that SOCS1 functions as an indispensable attenuator of IL-15 receptor signaling in developing CD8 thymocytes. (Blood. 2003;102:4115-4122)