title: Suppressor of cytokine signaling 1 attenuates IL-15 receptor signaling in CD8+ thymocytes.
abstract: SOCS1-/- mice die prematurely of increased interferon-gamma (IFNgamma) signaling with severe thymic atrophy and accelerated maturation of T cells. However, it was unclear whether the thymic defects were caused by SOCS1 deficiency or by increased IFNgamma signaling. Using SOCS1-/- IFNgamma-/- mice, we show in this study that SOCS1 deficiency skews thymocyte development toward CD8 lineage independently of IFNgamma. Fetal thymic organ cultures and intrathymic transfer of CD4-CD8- precursors into Rag1-/- mice show that the lineage skewing in SOCS1-/- mice is a T-cell autonomous defect. Interestingly, SOCS1 is not required for attenuating interleukin-7 (IL-7) signaling at the CD4-CD8- stage but is essential for regulating IL-15 and IL-2 signaling in CD8+ thymocytes. IL-15 selectively stimulates SOCS1-/- CD8+ thymocytes, inducing sustained signal transducer and activator of transcription 5 (STAT5) phosphorylation and massive proliferation. IL-15 also strongly up-regulates Bcl-xL and CD44 in CD8+ thymocytes lacking SOCS1. The SOCS1 gene is induced in CD4+ thymocytes by gammac cytokines, whereas CD8+ thymocytes constitutively express SOCS1 mRNA even in the absence of cytokine stimulation. Because many different cell types express IL-15, our results strongly suggest that SOCS1 functions as an indispensable attenuator of IL-15 receptor signaling in developing CD8+ thymocytes.
authors.affiliation: Rm 10-108, Ontario Cancer Institute, Princess Margaret Hospital, University Health Network, 610 University Ave, Toronto M5G 2M9, Canada.
authors.forename: Subburaj
authors.initials: S
authors.lastname: Ilangumaran
authors.forename: Sheela
authors.initials: S
authors.lastname: Ramanathan
authors.forename: Terry
authors.initials: T
authors.lastname: Ning
authors.forename: Jose
authors.initials: J
authors.lastname: La Rose
authors.forename: Brandon
authors.initials: B
authors.lastname: Reinhart
authors.forename: Philippe
authors.initials: P
authors.lastname: Poussier
authors.forename: Robert
authors.initials: R
authors.lastname: Rottapel
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D019070:Cell Lineage; D004268:DNA-Binding Proteins / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology; D007377:Interleukin-3 / Q000378:metabolism; D015851:Interleukin-7 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D008894:Milk Proteins; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000378:metabolism*; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013950:Thymus Gland / Q000166:cytology*; D015534:Trans-Activators / Q000378:metabolism; D051020:bcl-X Protein
chemical_list: C494812:Bcl2l1 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; C508025:Il15ra protein, mouse; D007377:Interleukin-3; D015851:Interleukin-7; D008894:Milk Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D051020:bcl-X Protein; D007371:Interferon-gamma