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Suppressor of Cytokine Signaling 1 Regulates IL-15 Receptor Signaling in CD8⁺CD44^high Memory T Lymphocytes ¹

Subburaj Ilangumaran^*, Sheela Ramanathan, Jose La Rose^*, Philippe Poussier^,, and Robert Rottapel^2,*,,,¶,||

^* Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, Sunnybrook and Women’s College Health Science Center, Departments of Immunology, Medicine, and ^¶ Medical Biophysics, University of Toronto, and ^|| St. Michael’s Hospital, Toronto, Canada

T lymphocyte survival, proliferation, and death in the periphery are dependent on several cytokines. Many of these cytokines induce the expression of suppressor of cytokine signaling-1 (SOCS1), a feedback inhibitor of JAK kinases. However, it is unclear whether the cytokines that regulate T lymphocyte homeostasis are critically regulated by SOCS1 in vivo. Using SOCS1^-/-IFN-^-/- mice we show that SOCS1 deficiency causes a lymphoproliferative disorder characterized by decreased CD4/CD8 ratio due to chronic accumulation of CD8⁺CD44^high memory phenotype T cells. SOCS1-deficient CD8⁺ T cells express elevated levels of IL-2R, show increased proliferative response to IL-15 and IL-2 in vitro, and undergo increased bystander proliferation and vigorous homeostatic expansion in vivo. Sorted CD8⁺CD44^high T cells from SOCS1^-/-IFN-^-/- mice respond 5 times more strongly than control cells, indicating that SOCS1 is a critical regulator of IL-15R signaling. Consistent with this idea, IL-15 stimulates sustained STAT5 phosphorylation in SOCS1-deficient CD8⁺ T cells. IL-15 strongly induces TNF- production in SOCS1-deficient CD8⁺ T cells, indicating that SOCS1 is also a critical regulator of CD8⁺ T cell activation by IL-15. However, IL-15 and IL-2 induce comparable levels of Bcl-2 and Bcl-x_L in SOCS1-deficient and SOCS1-sufficient CD8⁺ T cells, suggesting that cytokine receptor signals required for inducing proliferation and cell survival signals are not identical. These results show that SOCS1 differentially regulates common -chain cytokine signaling in CD8⁺ T cells and suggest that CD8⁺ T cell homeostasis is maintained by distinct mechanisms that control cytokine-mediated survival and proliferation signals.

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