Suppressor of Cytokine Signaling 1 Stringently Regulates Distinct Functions of IL-7 and IL-15 In Vivo during T Lymphocyte Development and Homeostasis1

SOCS1−/− mice accumulate within the thymus and periphery CD8+ lymphocytes that express memory cell markers and display heightened in vitro responses to common γ-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 TCRtg 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-TCRtg 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.