Suppressor of cytokine signaling-1 regulates signaling in response to interleukin-2 and other γc-dependent cytokines in peripheral T cells

Suppressor of cytokine signaling- 1 ( SOCS- 1) is an essential regulator of cytokine signaling. SOCS-1(-/-) mice die before weaning with a complex disease characterized by fatty degeneration and necrosis of the liver. This disease is mediated by interferon ( IFN) gamma as neonatal mortality fails to occur in SOCS-1(-/-) IFNgamma(-/-) mice. However, the immune system of healthy SOCS-1(-/-) IFNgamma(-/-) mice is dysregulated with a reduced ratio of CD4: CD8 T cells and increases in some aspects of T cell activation. SOCS-1(-/-) IFNgamma(-/-) mice also die before their wild type and IFNgamma(-/-) counterparts with a range of inflammatory conditions including pneumonia, gut infiltration, and skin ulceration, suggesting that SOCS- 1 controls not only IFNgamma signaling, but also other immunoregulatory factors. This study shows that T cells from SOCS- 1- deficient mice display hypersensitivity to cytokines that act through the gammac receptor. SOCS- 1 expression is induced by interleukin ( IL) 2, IL- 4, IL- 7, and IL- 15, and SOCS- 1-deficient T cells show increased proliferation and prolonged survival in response to IL- 2 and IL- 4. Furthermore, IL- 2 induced increased STAT5 phosphorylation and CD44 expression in SOCS- 1- deficient T cells compared with controls. Hypersensitivity to gammac- dependent cytokines may contribute to abnormal T cell function, as well as the pathology observed in mice lacking SOCS- 1.