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Defective Thymocyte Development and Perturbed Homeostasis of T cells in STAT-Induced STAT Inhibitor-1/Suppressors of Cytokine Signaling-1 Transgenic Mice¹

Minoru Fujimoto^*, Tetsuji Naka^*, Reiko Nakagawa, Yoshinori Kawazoe^*, Yoshiaki Morita^*, Akihiro Tateishi, Koichi Okumura^§, Masashi Narazaki^* and Tadamitsu Kishimoto^2,¶

Departments of ^* Medicine III and Microbiology, Osaka University Medical School; ^§ Biomolecular Engineering Research Institute; and ^¶ Osaka University, Suita City, Osaka, Japan

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-, 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 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 -chain or Janus kinase-3, suggesting that transgene-derived SSI-1 inhibits the functions of common -chain-using cytokines. Taken together, these results suggest that SSI-1 can also inhibit a wide variety of cytokines in vivo.

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