Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other gamma c-dependent cytokines in peripheral T cells.
Suppressor of cytokine signaling-1 (SOCS-1) is an essential regulator of cytokine signaling. SOCS-1-/- mice die before weaning with a complex disease characterized by fatty degeneration and necrosis of the liver. This disease is mediated by interferon (IFN) gamma as neonatal mortality fails to occur in SOCS-1-/-IFNgamma-/- mice. However, the immune system of healthy SOCS-1-/-IFNgamma-/- mice is dysregulated with a reduced ratio of CD4:CD8 T cells and increases in some aspects of T cell activation. SOCS-1-/-IFNgamma-/- mice also die before their wild type and IFNgamma-/- counterparts with a range of inflammatory conditions including pneumonia, gut infiltration, and skin ulceration, suggesting that SOCS-1 controls not only IFNgamma signaling, but also other immunoregulatory factors. This study shows that T cells from SOCS-1-deficient mice display hypersensitivity to cytokines that act through the gammac receptor. SOCS-1 expression is induced by interleukin (IL) 2, IL-4, IL-7, and IL-15, and SOCS-1-deficient T cells show increased proliferation and prolonged survival in response to IL-2 and IL-4. Furthermore, IL-2 induced increased STAT5 phosphorylation and CD44 expression in SOCS-1-deficient T cells compared with controls. Hypersensitivity to gammac-dependent cytokines may contribute to abnormal T cell function, as well as the pathology observed in mice lacking SOCS-1.
Cornish
Ann L
AL
The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria 3050, Australia.
Chong
Mark M
MM
Davey
Gayle M
GM
Darwiche
Rima
R
Nicola
Nicos A
NA
Hilton
Douglas J
DJ
Kay
Thomas W
TW
Starr
Robyn
R
Alexander
Warren S
WS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000494:pharmacology*; D005260:Female; D007376:Interleukin-2 / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D002352:Carrier Proteins; D016207:Cytokines; D007376:Interleukin-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins