Suppressor of cytosine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes

SOCS1(-/-) mice die prematurely of increased interferon-gamma (IFNgamma) 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 IFNgamma signaling. Using SOCS1(-/-) IFNgamma(-/-) mice, we show in this study that SOCS1 deficiency skews thymocyte development toward CD8 lineage independently of IFNgamma. 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 gamma(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. (C) 2003 by The American Society of Hematology.