Defective thymocyte development and perturbed homeostasis of T cells in STAT-induced STAT inhibitor-1/suppressors of cytokine signaling-1 transgenic mice.
Previous experiments have shown that STAT-induced STAT inhibitor-1 (SSI-1; also named suppressors of cytokine signaling-1 (SOCS-1) or Janus kinase binding protein) is predominantly expressed in lymphoid organs and functions in vitro as a negative regulator of cytokine signaling. To determine the function of SOCS-1 in vivo, we generated SSI-1 transgenic mice using the lck proximal promoter that drives transgene expression in T cell lineage. In thymocytes expressing SSI-1 transgene, tyrosine phosphorylation of STATs in response to cytokines such as IFN-gamma, IL-6, and IL-7 was inhibited, suggesting that SSI-1 suppresses cytokine signaling in primary lymphocytes. In addition, lck-SSI-1 transgenic mice showed a reduction in the number of thymocytes as a result of the developmental blocking during triple-negative stage. They also exhibited a relative increase in the percentage of CD4+ T cells, a reduction in the number of gammadelta T cells, as well as the spontaneous activation and increased apoptosis of peripheral T cells. Thus, enforced expression of SSI-1 disturbs the development of thymocytes and the homeostasis of peripheral T cells. All these features of lck-SSI-1 transgenic mice strikingly resemble the phenotype of mice lacking common gamma-chain or Janus kinase-3, suggesting that transgene-derived SSI-1 inhibits the functions of common gamma-chain-using cytokines. Taken together, these results suggest that SSI-1 can also inhibit a wide variety of cytokines in vivo.
Fujimoto
M
M
Departments of Medicine III and Microbiology, Osaka University Medical School, Osaka, Japan.
Naka
T
T
Nakagawa
R
R
Kawazoe
Y
Y
Morita
Y
Y
Tateishi
A
A
Okumura
K
K
Narazaki
M
M
Kishimoto
T
T
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics; D005260:Female; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D053616:Janus Kinase 3; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000235:genetics; D008231:Lymphopenia / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics; D012097:Repressor Proteins; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism / Q000473:pathology*
D002352:Carrier Proteins; D016207:Cytokines; D018121:Receptors, Cytokine; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D011505:Protein-Tyrosine Kinases; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)