Defective Thymocyte Development and Perturbed Homeostasis of T cells in STAT-Induced STAT Inhibitor-1/Suppressors of Cytokine Signaling-1 Transgenic Mice

• Published in: The Journal of immunology (1950) Vol. 165; no. 4; pp. 1799 - 1806
• Main Authors: Fujimoto, Minoru, Naka, Tetsuji, Nakagawa, Reiko, Kawazoe, Yoshinori, Morita, Yoshiaki, Tateishi, Akihiro, Okumura, Koichi, Narazaki, Masashi, Kishimoto, Tadamitsu
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15-08-2000
• Subjects: Animals; Apoptosis - genetics; Apoptosis - immunology; Carrier Proteins - genetics; Carrier Proteins - physiology; Cell Differentiation - genetics; Cell Differentiation - immunology; Cytokines - antagonists & inhibitors; Cytokines - deficiency; Cytokines - genetics; Female; g-Interferon; Homeostasis - genetics; Homeostasis - immunology; Immunologic Memory - genetics; Immunophenotyping; Janus Kinase 3; Lymphocyte Activation - genetics; Lymphocyte Count; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - genetics; Lymphopenia - genetics; Lymphopenia - immunology; Lymphopenia - pathology; Mice; Mice, Transgenic; Pregnancy; Protein-Tyrosine Kinases - deficiency; Protein-Tyrosine Kinases - genetics; Receptors, Cytokine - deficiency; Receptors, Cytokine - genetics; Repressor Proteins; Signal Transduction - genetics; Signal Transduction - immunology; SOCS-1 protein; SSI-1 protein; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes - enzymology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.4.1799

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.