Suppressor of Cytokine Signaling 1 Stringently Regulates Distinct Functions of IL-7 and IL-15 In Vivo during T Lymphocyte Development and Homeostasis

SOCS1(-/-) mice accumulate within the thymus and periphery CD8(+) lymphocytes that express memory cell markers and display heightened in vitro responses to common gamma-chain cytokines. To investigate whether dysregulated homeostasis of T lymphocytes and acquisition of memory phenotype by CD8(+) cells in SOCS1(-/-) mice were mediated by IL-7 and/or IL-15 in vivo, we have generated SOCS1(-/-)IL-7(-/-), SOCS1(-/-)IL-15(-/-) and SOCS1(-/-)IL-7(-/-)IL-15(-/-) mice. We observed that in mice lacking SOCS1, either IL-7 or IL-15 skewed thymocyte development toward CD8 lineage, whereas IL-15 is the principal mediator of dysregulated homeostasis in the periphery. Homeostatic proliferation of SOCS1(-/-) CD8(+) lymphocytes in Rag1(-/-), Rag1(-/-)IL-7(-/-), Rag1(-/-)IL-15(-/-), and Rag1(-/-)IL-7(-/-)IL-15(-/-) mice showed that SOCS1 deficiency did not overcome the requirement for IL-7 and IL-15 to sustain homeostatic expansion. Differential expression of memory phenotype markers CD44, CD122, and Ly6C by SOCS1(-/-)IL-15(-/-) CD8(+) lymphocytes suggest that multiple signals contributed to the memory cell differentiation program. To address whether increased IL-15 responsiveness of SOCS1(-/-) CD8(+) lymphocytes required prior TCR sensitization, we generated SOCS1(-/-) H-Y TCR transgenic (Tg) mice. Using female SOCS1(-/-) H-Y TCR(tg) mice in Rag1(+/+) and Rag1(-/-) backgrounds, we show that acquisition of the memory phenotype by SOCS1-deficient CD8(+) lymphocytes did not require prior antigenic stimulation, but required the presence of activated T cells. SOCS1 deficiency accelerated the maturation of CD8 single-positive thymocytes expressing Tg TCR, but did not compromise negative selection in HY-TCR(tg) males. Our findings illustrate distinct functions for IL-7 and IL-15 in T lymphocyte development and homeostasis, and stringent regulation of these processes by SOCS1.