SOCS3 is a suppressor of γc cytokine signaling and constrains generation of murine Foxp3+ regulatory T cells.,European Journal of Immunology

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SOCS3 is a suppressor of γc cytokine signaling and constrains generation of murine Foxp3+ regulatory T cells.
European Journal of Immunology ( IF 4.5 ) Pub Date : 2020-03-06 , DOI: 10.1002/eji.201948307
Megan A Luckey ₁ , Tae-Hyoun Kim ₁ , Praveen Prakhar ₁ , Hilary R Keller _{1,

2} , Assiatu Crossman ₁ , Seeyoung Choi ₃ , Paul E Love ₃ , Scott T R Walsh ₄ , Jung-Hyun Park ₁

Affiliation

SOCS3 is a cytosolic inhibitor of cytokine signaling that suppresses the activation of cytokine receptor‐associated JAK kinases. Mechanistically, SOCS3 is recruited to a site in the cytokine receptors known as the SOCS3‐interaction motif, and then binds JAK molecules to inhibit their kinase activity. The SOCS3‐interaction motif is found in receptors of the gp130 cytokine family but mostly absent from other cytokine receptors, including γc. Thus, SOCS3 has been considered a selective suppressor of gp130 family cytokines, but not γc cytokines. Considering that γc signaling induces SOCS3 expression in T cells, here we revisited the role of SOCS3 on γc signaling. Using SOCS3 transgenic mice, we found that increased abundance of SOCS3 not only suppressed signaling of the gp130 family cytokine IL‐6, but also signaling of the γc family cytokine IL‐7. Consequently, SOCS3 transgenic mice were impaired in IL‐7‐dependent T cell development in the thymus and the homeostasis of mature T cells in peripheral tissues. Moreover, enforced SOCS3 expression interfered with the generation of Foxp3⁺ regulatory T cells that requires signaling by the γc family cytokine IL‐2. Collectively, we report an underappreciated role for SOCS3 in suppressing γc cytokine signaling, effectively expanding its scope of target cytokines in T cell immunity.

中文翻译：

SOCS3 是 γc 细胞因子信号传导的抑制因子，可抑制鼠 Foxp3+ 调节性 T 细胞的生成。

SOCS3 是一种细胞因子信号传导的胞质抑制剂，可抑制细胞因子受体相关 JAK 激酶的激活。从机制上讲，SOCS3 被募集到细胞因子受体中称为 SOCS3 相互作用基序的位点，然后与 JAK 分子结合以抑制其激酶活性。SOCS3 相互作用基序存在于 gp130 细胞因子家族的受体中，但在包括 γc 在内的其他细胞因子受体中大多不存在。因此，SOCS3 被认为是 gp130 家族细胞因子的选择性抑制因子，而不是 γc 细胞因子。考虑到 γc 信号在 T 细胞中诱导 SOCS3 表达，我们在这里重新审视了 SOCS3 在 γc 信号中的作用。使用 SOCS3 转基因小鼠，我们发现增加的 SOCS3 丰度不仅抑制了 gp130 家族细胞因子 IL-6 的信号传导，而且还抑制了 γc 家族细胞因子 IL-7 的信号传导。因此，SOCS3 转基因小鼠的胸腺中 IL-7 依赖性 T 细胞发育和外周组织中成熟 T 细胞的稳态受损。此外，强制 SOCS3 表达干扰了 Foxp3 的生成⁺需要 γc 家族细胞因子 IL-2 信号传导的调节性 T 细胞。总的来说，我们报告了 SOCS3 在抑制 γc 细胞因子信号传导中被低估的作用，有效地扩大了其在 T 细胞免疫中的靶细胞因子范围。

更新日期：2020-03-06

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