Microbiota-reactive CD4⁺ T memory (T_M) cells are generated during intestinal infections and inflammation, and can revert to pathogenic CD4⁺ T effector (T_E) cells, resulting in chronicity of inflammatory bowel disease (IBD). Unlike T_E cells, T_M cells have a low rate of metabolism unless they are activated by reencountering cognate antigen. Here, we show that the combination of cell activation and metabolic checkpoint inhibition (CAMCI), by targeting key metabolic regulators mTORC and AMPK, resulted in cell death and anergy, but enhanced the induction of the regulatory subset. Parenteral application of this treatment with a synthetic peptide containing multiple flagellin T cell epitopes (MEP1) and metabolic inhibition successfully prevented the development of CD4⁺ T cell–driven colitis. Microbiota-specific CD4⁺ T cells, especially the pathogenic T_E subsets, were decreased 10-fold in the intestinal lamina propria. Furthermore, using the CAMCI strategy, we were able to prevent antigen-specific T_M cell formation upon initial antigen encounter, and ablate existing T_M cells upon reactivation in mice, leading to an altered transcriptome in the remaining CD4⁺ T cells after ablation. Microbiota flagellin–specific CD4⁺ T cells from patients with Crohn’s disease were ablated in a similar manner after CAMCI in vitro, with half of the antigen-specific T cells undergoing cell death. These results indicate that parenteral activation of microbiota-specific CD4⁺ T cells with concomitant metabolic inhibition is an effective way to ablate pathogenic CD4⁺ T_M cells and to induce T regulatory (T_reg) cells that provide antigen-specific and bystander suppression, supporting a potential immunotherapy to prevent or ameliorate IBD.

菌群反应性CD4 ⁺ T寄存器（T_中号期间肠道感染和炎症产生）的细胞，并能恢复到致病CD4 ⁺ T效应（T _ë）细胞，导致炎性肠病（IBD）的慢性。与 T _E细胞不同，T _M细胞代谢率低，除非它们被重新遇到同源抗原激活。在这里，我们展示了细胞激活和代谢检查点抑制 (CAMCI) 的组合，通过靶向关键代谢调节剂 mTORC 和 AMPK，导致细胞死亡和无反应性，但增强了调节子集的诱导。使用含有多个鞭毛蛋白 T 细胞表位 (MEP1) 和代谢抑制的合成肽进行胃肠外治疗，成功阻止了 CD4 ⁺ T 细胞驱动的结肠炎的发展。肠道固有层中微生物群特异性 CD4 ⁺ T 细胞，尤其是致病性 T _E亚群减少了 10 倍。此外，使用 CAMCI 策略，我们能够防止抗原特异性 T_M细胞在最初遇到抗原时形成，并在小鼠中重新激活后消融现有的 T _M细胞，导致消融后剩余 CD4 ⁺ T 细胞的转录组发生改变。来自克罗恩病患者的微生物群鞭毛蛋白特异性 CD4 ⁺ T 细胞在体外 CAMCI 后以类似的方式被消融，其中一半的抗原特异性 T 细胞经历细胞死亡。这些结果表明肠道外激活微生物群特异性 CD4 ⁺ T 细胞并伴随代谢抑制是消融致病性 CD4 ⁺ T _M细胞和诱导 T 调节（T _reg) 提供抗原特异性和旁观者抑制的细胞，支持潜在的免疫疗法以预防或改善 IBD。