Suppressor of cytokine signaling-1 has IFN-gamma-independent actions in T cell homeostasis.
Suppressor of cytokine signaling (SOCS)-1 is a member of a family of proteins that negatively regulate cytokine signaling pathways. We have previously established that SOCS-1 is a key regulator of IFN-gamma signaling and that IFN-gamma is responsible for the complex inflammatory disease that leads to the death of SOCS-1-deficient mice. In this study, we provide evidence that SOCS-1 is also a critical regulator of IFN-gamma-independent immunoregulatory factors. Mice lacking both SOCS-1 and IFN-gamma, although outwardly healthy, have clear abnormalities in their immune system, including a reduced ratio of CD4:CD8 T cells in lymphoid tissues and increased expression of T cell activation markers. To examine the contribution of TCR Ag specificity to these immune defects, we have generated two lines of SOCS-1-deficient mice expressing a transgenic TCR specific for an exogenous Ag, OVA (OT-I and OT-II). Although TCR transgenic SOCS-1(-/-) mice have a longer lifespan than nontransgenic SOCS-1(-/-) mice, they still die as young adults with inflammatory disease and the TCR transgenic SOCS-1(-/-) T cells appear activated despite the absence of OVA. This suggests that both Ag-dependent and -independent mechanisms contribute to the disease in SOCS-1-deficient mice. Thus, SOCS-1 is a critical regulator of T cell activation and homeostasis, and its influence extends beyond regulating IFN-gamma signaling.
Cornish
Ann L
AL
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Davey
Gayle M
GM
Metcalf
Donald
D
Purton
Jared F
JF
Corbin
Jason E
JE
Greenhalgh
Christopher J
CJ
Darwiche
Rima
R
Wu
Li
L
Nicola
Nicos A
NA
Godfrey
Dale I
DI
Heath
William R
WR
Hilton
Douglas J
DJ
Alexander
Warren S
WS
Starr
Robyn
R
D000818:Animals; D016516:CD4-CD8 Ratio; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000502:physiology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005333:Fetus; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009924:Organ Culture Techniques; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology
D002352:Carrier Proteins; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D011948:Receptors, Antigen, T-Cell; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma