title: Suppressor of cytokine signaling-1 has IFN-gamma-independent actions in T cell homeostasis.
abstract: 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Ann L
authors.initials: AL
authors.lastname: Cornish
authors.forename: Gayle M
authors.initials: GM
authors.lastname: Davey
authors.forename: Donald
authors.initials: D
authors.lastname: Metcalf
authors.forename: Jared F
authors.initials: JF
authors.lastname: Purton
authors.forename: Jason E
authors.initials: JE
authors.lastname: Corbin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Greenhalgh
authors.forename: Rima
authors.initials: R
authors.lastname: Darwiche
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Nicola
authors.forename: Dale I
authors.initials: DI
authors.lastname: Godfrey
authors.forename: William R
authors.initials: WR
authors.lastname: Heath
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Robyn
authors.initials: R
authors.lastname: Starr
mesh_terms: 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
chemical_list: 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