Tonic TCR and IL-1-beta signaling mediate phenotypic alterations of naive CD4+ T cells

Inert naive CD4+ T (TN) cells differentiate into functional helper T or regulatory T (Treg) cell subsets upon encountering antigens, enabling properly-directed immune responses. Although all TN cells can differentiate into any Th and Treg cell subsets, recent studies have revealed some heterogeneity among TN cells. Here, by developing novel reporter mice that detect ongoing T cell receptor (TCR) signaling, we revealed the effects of tonic TCR signaling on TN cells, while unexpectedly finding that IL-1-beta affects TN cell characteristics. IL-1-beta signals to TN cells particularly in the spleen and in inflamed tissues, attenuating their differentiation potential to Treg cells. A mouse colitis model revealed reversible effects of IL-1-beta on TN cells' colitogenic activities. Aberrant regulation of IL-1-betatargets in TN cells was detected in colitis patients, showing its association with therapeutic response to anti-TNF therapies. Our work revealed the IL-1-beta-TN cell axis as a novel regulator of immune response.初始CD4+ T（TN）细胞在遭遇抗原后可分化为功能性辅助性T（Th）细胞或调节性T（Treg）细胞亚群，从而介导精准定向的免疫应答。尽管所有TN细胞均具备分化为各类Th细胞及Treg细胞亚群的潜能，但近期研究揭示了TN细胞群体内部存在异质性。本研究通过构建可检测活化中T细胞受体（TCR）信号的新型报告基因小鼠，阐明了基础TCR信号对TN细胞的调控作用，并意外发现白细胞介素-1β（IL-1β）可影响TN细胞的生物学特性。IL-1β主要在脾脏及炎症组织中作用于TN细胞，削弱其向Treg细胞分化的潜能。小鼠结肠炎模型实验证实，IL-1β对TN细胞的致结肠炎活性具有可逆调控作用。研究人员在结肠炎患者体内检测到TN细胞中IL-1β靶基因的调控异常，这表明该异常与抗TNF治疗的临床应答存在关联。本研究揭示了IL-1β-TN细胞轴作为新型免疫应答调控通路的关键作用。