SOCS1^-/- mice die prematurely of increased interferon-γ (IFNγ) 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 IFNγ signaling. Using SOCS1^-/-IFNγ^-/- mice, we show in this study that SOCS1 deficiency skews thymocyte development toward CD8 lineage independently of IFNγ. 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 up-regulates Bcl-xL and CD44 in CD8⁺ thymocytes lacking SOCS1. The SOCS1 gene is induced in CD4⁺ thymocytes by γ_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)