Cytokines are important intercellular communication tools for immunity. Most cytokines utilize the JAK-STAT and Ras-ERK pathways to promote gene transcription and proliferation; however, this signaling is tightly regulated. The suppressor of cytokine signaling (SOCS) family and SPRED family are a representative negative regulators of the JAK-STAT pathway and the Ras-ERK pathway, respectively. The SOCS family regulates the differentiation and function of CD4⁺ T cells, CD8⁺ T cells, and regulatory T cells, and is involved in immune tolerance, anergy, and exhaustion. SPRED family proteins have been shown to inactivate Ras by recruiting the Ras-GTPase neurofibromatosis type 1 (NF1) protein. Human genetic analysis has shown that SOCS family members are strongly associated with autoimmune diseases, allergies, and tumorigenesis, and SPRED1 is involved in NF1-like syndromes and tumors. We also identified the NR4a family of nuclear receptors as a key transcription factor for immune tolerance that suppresses cytokine expression and induces various immuno-regulatory molecules including SOCS1.

细胞因子是免疫的重要细胞间通讯工具。大多数细胞因子利用 JAK-STAT 和 Ras-ERK 通路来促进基因转录和增殖；然而，这种信号受到严格监管。细胞因子信号传导抑制因子 (SOCS) 家族和 SPRED 家族分别是 JAK-STAT 通路和 Ras-ERK 通路的代表性负调节因子。SOCS 家族调节 CD4 ⁺ T 细胞的分化和功能，CD8 ⁺T 细胞和调节性 T 细胞，并参与免疫耐受、无反应性和衰竭。已显示 SPRED 家族蛋白通过募集 Ras-GTPase 1 型神经纤维瘤病 (NF1) 蛋白使 Ras 失活。人类遗传分析表明，SOCS 家族成员与自身免疫性疾病、过敏和肿瘤发生密切相关，而 SPRED1 与 NF1 样综合征和肿瘤有关。我们还确定 NR4a 核受体家族是免疫耐受的关键转录因子，可抑制细胞因子表达并诱导包括 SOCS1 在内的各种免疫调节分子。