A regulatory role for suppressor of cytokine signaling-1 in Th polarization in vivo

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Abstract
Suppressor of cytokine signaling (SOCS)‐1 is an inhibitory molecule for JAK, and its deficiency in mice leads to lymphocyte‐dependent multi‐organ disease and perinatal death. Crossing of SOCS‐1–/– mice on an IFN‐γ–/–, STAT1–/– and STAT6–/– background revealed that the fatal disease of SOCS‐1–/– mice is also dependent on IFN‐γ/STAT1 and IL‐4/STAT6 signaling pathways. Since IFN‐γ and IL‐4 are representative Th1 and Th2 cytokines respectively, here we investigated the role of SOCS‐1 in Th differentiation. Freshly isolated SOCS‐1–/– CD4+ T cells stimulated with anti‐CD3 rapidly produced larger amounts of IFN‐γ and IL‐4 than control cells, suggesting that these mutant T cells had already differentiated into Th1 and Th2 cells in vivo. In addition, SOCS‐1+/– CD4+ T cells cultured in vitro produced significantly larger amounts of IFN‐γ and IL‐4 than SOCS‐1+/+ cells. Similarly, SOCS‐1+/– CD4+ T cells produced more IFN‐γ and IL‐4 than SOCS‐1+/+ cells after infection with Listeria monocytogenes and Nippostrongyrus braziliensis respectively. Since IL‐12‐induced STAT4 and IL‐4‐induced STAT6 activation is sustained in SOCS‐1–/– T cells, the enhanced Th functions in SOCS‐1–/– and SOCS‐1+/– mice appear to be due to the enhanced effects of these cytokines. These results suggest that SOCS‐1 plays a regulatory role in both Th1 and Th2 polarizations.

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