Regulation of cytokine-driven functional differentiation of CD8 T cells by suppressor of cytokine signaling 1 controls autoimmunity and preserves their proliferative capacity toward foreign antigens.
We have previously shown that naive CD8 T cells exposed to IL-7 or IL-15 in the presence of IL-21 undergo Ag-independent proliferation with concomitant increase in TCR sensitivity. In this study, we examined whether CD8 T cells that accumulate in suppressor of cytokine signaling 1 (SOCS1)-deficient mice because of increased IL-15 signaling in vivo would respond to an autoantigen expressed at a very low level using a mouse model of autoimmune diabetes. In this model, P14 TCR transgenic CD8 T cells (P14 cells) adoptively transferred to rat insulin promoter-glycoprotein (RIP-GP) mice, which express the cognate Ag in the islets, do not induce diabetes unless the donor cells are stimulated by exogenous Ag. Surprisingly, SOCS1-deficient P14 cells, which expanded robustly following IL-15 stimulation, proliferated poorly in response to Ag and failed to cause diabetes in RIP-GP mice. SOCS1-deficient CD8 T cells expressing a polyclonal TCR repertoire also showed defective expansion following in vivo Ag stimulation. Notwithstanding the Ag-specific proliferation defect, SOCS1-null P14 cells produced IFN-gamma and displayed potent cytolytic activity upon Ag stimulation, suggesting that SOCS1-null CD8 T cells underwent cytokine-driven functional differentiation that selectively compromised their proliferative response to Ag but not to cytokines. Cytokine-driven homeostatic expansion in lymphopenic RIP-GP mice allowed SOCS1-null, but not wild-type, P14 cells to exert their pathogenic potential even without Ag stimulation. These findings suggest that by attenuating cytokine-driven proliferation and functional differentiation, SOCS1 not only controls the pathogenicity of autoreactive cells but also preserves the ability of CD8 T cells to proliferate in response to Ags.
Immunology Division, Department of Pediatrics, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, Canada. Sheela.Ramanathan@Usherbrooke.ca
Sheela
S
Ramanathan
Stephanie
S
Dubois
Julien
J
Gagnon
Chantal
C
Leblanc
Sanjeev
S
Mariathasan
Gerardo
G
Ferbeyre
Robert
R
Rottapel
Pamela S
PS
Ohashi
Subburaj
S
Ilangumaran
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051381:Rats; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins