Abstract

The type I interferons are central to a vast array of immunological functions. The production of these immune-modulatory molecules is initiated at the early stages of the innate immune responses and, therefore, plays a dominant role in shaping downstream events in both innate and adaptive immunity. Indeed, the major role of IFN-α/β is the induction of priming states, relevant for the functional differentiation of T lymphocyte subsets. Among T-cell subtypes, the CD4⁺CD25⁺Foxp3⁺ T regulatory cells (T_regs) represent a specialized subset of CD4⁺ T cells with a critical role in maintaining peripheral tolerance and immune homeostasis. Although the role of type I interferons in maintaining the function of thymus-derived T_regs has been previously described, the direct contribution of these innate factors to peripheral T_reg (pT_reg) and induced T_reg (iT_reg) differentiation and suppressive function is still unclear. We now show that, under tolerogenic conditions, IFN-α/β play a critical role in antigen-specific and also polyclonal naive CD4⁺ T-cell conversion into peripheral antigen-specific CD4⁺CD25⁺Foxp3⁺ T_regs and inhibit CD4⁺ T helper (T_h) cell expansion in mice. While type I interferons sustain the expression and the activation of the transcription master regulators Foxp3, Stat3 and Stat5, these innate molecules reciprocally inhibit T_h17 cell differentiation. Altogether, these results indicate a new pivotal role of IFN-α/β on pT_reg differentiation and induction of peripheral tolerance, which may have important implications in the therapeutic control of inflammatory disorders, such as of autoimmune diseases.

中文翻译：

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I型干扰素在耐受性条件下诱导外周T调节细胞分化

摘要

I 型干扰素是众多免疫功能的核心。这些免疫调节分子的产生始于先天免疫反应的早期阶段，因此在形成先天免疫和适应性免疫的下游事件中起主导作用。事实上，IFN-α/β 的主要作用是诱导启动状态，这与 T 淋巴细胞亚群的功能分化有关。在 T 细胞亚型中，CD4 ⁺ CD25 ⁺ Foxp3 ⁺ T 调节细胞 (T _regs ) 代表 CD4 ⁺T 细胞在维持外周耐受和免疫稳态中起关键作用。尽管之前已经描述了I 型干扰素在维持胸腺来源的 T reg 功能中的作用_{，但这些先天因素对外周 T reg} (pT _reg ) 和诱导 T _reg (iT _reg ) 分化和抑制功能的直接贡献是还不清楚。我们现在表明，在耐受性条件下，IFN-α/β 在抗原特异性和多克隆初始 CD4 ⁺ T 细胞转化为外周抗原特异性 CD4 ⁺ CD25 ⁺ Foxp3 ⁺ T _{regs中起关键作用}并抑制小鼠 CD4 ⁺ T 辅助 (T _h ) 细胞扩增。虽然 I 型干扰素维持转录主调节因子 Foxp3、Stat3 和 Stat5 的表达和激活，但这些先天分子相互抑制 Th ₁₇细胞分化。总之，这些结果表明 IFN-α/β 在 pT _reg分化和诱导外周耐受方面具有新的关键作用，这可能对炎症性疾病（例如自身免疫性疾病）的治疗控制具有重要意义。