The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4⁺CD44⁺Foxp3⁻CD73⁺FR4⁺ anergic (Tan) cells expands the CD4⁺Foxp3⁺ (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila commensal bacteria can induce anergy and drive conversion of naive CD4⁺CD44^-Foxp3⁻ T (Tn) cells to the Treg lineage. Overall, data presented here suggest that Tan induction helps the Treg repertoire to become optimally balanced to provide tolerance toward ubiquitous and microbiome-derived epitopes, improving host ability to avert systemic autoimmunity and intestinal inflammation.

T 细胞无反应性诱导作为支持自我耐受的关键机制的生理作用仍未明确，诱导无反应性的天然抗原在很大程度上是未知的。在本报告中，我们使用 TCR 测序显示 CD4 ⁺ CD44 ⁺ Foxp3 ⁻ CD73 ⁺ FR4 ⁺无能 (Tan) 细胞的募集扩展了 CD4 ⁺ Foxp3 ⁺ (Tregs) 库。接下来，我们报告了由于 Foxp3 的 CNS1 区域突变或长期暴露于选择的自身肽导致外周诱导的 Tregs (pTregs) 形成的阻断导致 Tan 细胞的积累。最后，我们表明来自Akkermansia muciniphila的微生物抗原共生细菌可诱导无能并驱动幼稚 CD4 ⁺ CD44 ^- Foxp3 ^- T (Tn) 细胞向 Treg 谱系的转化。总的来说，这里提供的数据表明，Tan 诱导有助于 Treg 库达到最佳平衡，以提供对普遍存在和微生物组衍生表位的耐受性，从而提高宿主避免全身性自身免疫和肠道炎症的能力。