Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
Department of Microbiology and Immunology, University of Minnesota Medical School, Minneapolis, MN, USA.
Nature. 2022 Jul;607(7920):762-768. doi: 10.1038/s41586-022-04916-6. Epub 2022 Jul 6.
Gastrointestinal health depends on the adaptive immune system tolerating the foreign proteins in food. This tolerance is paradoxical because the immune system normally attacks foreign substances by generating inflammation. Here we addressed this conundrum by using a sensitive cell enrichment method to show that polyclonal CD4 T cells responded to food peptides, including a natural one from gliadin, by proliferating weakly in secondary lymphoid organs of the gut-liver axis owing to the action of regulatory T cells. A few food-specific T cells then differentiated into T follicular helper cells that promoted a weak antibody response. Most cells in the expanded population, however, lacked canonical T helper lineage markers and fell into five subsets dominated by naive-like or T follicular helper-like anergic cells with limited capacity to form inflammatory T helper 1 cells. Eventually, many of the T helper lineage-negative cells became regulatory T cells themselves through an interleukin-2-dependent mechanism. Our results indicate that exposure to food antigens causes cognate CD4 naive T cells to form a complex set of noncanonical hyporesponsive T helper cell subsets that lack the inflammatory functions needed to cause gut pathology and yet have the potential to produce regulatory T cells that may suppress it.
胃肠道健康依赖于适应性免疫系统耐受食物中的外来蛋白质。这种耐受性是自相矛盾的，因为免疫系统通常通过引发炎症来攻击外来物质。在这里，我们使用一种敏感的细胞富集方法来解决这个难题，结果表明，多克隆 CD4 T 细胞通过调节性 T 细胞的作用，在胃肠道-肝脏轴的次级淋巴器官中微弱地增殖，对食物肽（包括来自麦醇溶蛋白的天然肽）产生反应。然后，一些食物特异性 T 细胞分化为滤泡辅助 T 细胞，促进了微弱的抗体反应。然而，在扩增的群体中，大多数细胞缺乏经典的 T 辅助谱系标志物，并分为五个亚群，主要由类似幼稚或滤泡辅助样无反应性细胞组成，形成炎症性 T 辅助 1 细胞的能力有限。最终，许多 T 辅助谱系阴性细胞通过白细胞介素-2 依赖的机制自身成为调节性 T 细胞。我们的研究结果表明，食物抗原的暴露导致同源 CD4 幼稚 T 细胞形成了一套复杂的非典型低反应性 T 辅助细胞亚群，这些亚群缺乏引起肠道病理学所需的炎症功能，但具有产生可能抑制其功能的调节性 T 细胞的潜力。
