title: Regulation of IL-21 signaling by suppressor of cytokine signaling-1 (SOCS1) in CD8(+) T lymphocytes.
abstract: Mice lacking the gene for suppressor of cytokine signaling 1 (SOCS1) show defective homeostasis of T lymphocytes due to accumulation of CD8(+) T cells, resulting at least partly from dysregulated IL-15 signaling. IL-15 alone does not stimulate proliferation of naïve CD8 T cells, but can synergize with IL-21 to induce proliferation, suggesting a potential role for IL-21 in the defective homeostasis of CD8(+) T lymphocytes in SOCS1(-/-) mice. Since IL-21 strongly induced SOCS1 mRNA in CD8(+) T cells, we investigated whether SOCS1 regulates their response to IL-21. CD8(+) T cells isolated from SOCS1-deficient mice proliferated vigorously in response to IL-21+IL-15. In CD8(+) T lymphocytes expressing transgenic TCR, IL-21+IL-7 provided a stronger stimulus to naïve cells whereas IL-15+IL-21 potently stimulated memory cells. Compared to truly naïve or memory cells, SOCS1(-/-) H-Y TCR(+) CD8(+) T cells displayed CD44(lo)Ly6C(hi)CD122(int)CD127(lo) partial memory phenotype and exhibited stronger response to IL-15+IL-21 than truly naïve cells. In SOCS1(-/-) CD8(+) T cells, IL-21 caused greater reduction in IL-15 threshold for activation in a dose-dependent manner. SOCS1 deficiency did not modulate IL-21Ralpha expression or sensitivity to IL-21, but delayed the loss of IL-21-induced phospho-STAT3 signal. These results show that SOCS1 is a critical regulator of IL-21 signaling in CD8(+) T cells, and support the notion that sustained IL-21 signaling might also contribute to the aberrant T cell homeostasis in SOCS1-deficient mice.
authors.affiliation: Immunology Division, Department of Pediatrics, Faculty of Medicine, University of Sherbrooke, 3001-12th Avenue North, Sherbrooke, QC, Canada.
authors.forename: Julien
authors.initials: J
authors.lastname: Gagnon
authors.forename: Sheela
authors.initials: S
authors.lastname: Ramanathan
authors.forename: Chantal
authors.initials: C
authors.lastname: Leblanc
authors.forename: Subburaj
authors.initials: S
authors.lastname: Ilangumaran
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006182:H-Y Antigen / Q000276:immunology; D018960:Hyaluronan Receptors / Q000276:immunology; D007156:Immunologic Memory / Q000187:drug effects; D019409:Interleukin-15 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D016207:Cytokines; D006182:H-Y Antigen; D018960:Hyaluronan Receptors; D019409:Interleukin-15; D007378:Interleukins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D050796:STAT3 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000098546:Interleukin-21