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

Sheela Ramanathan^*, Julien Gagnon^*, Chantal Leblanc^*, Robert Rottapel and Subburaj Ilangumaran^2,*

^* Immunology Division, Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Canada; and Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Toronto, Canada

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

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