Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4⁺ T cells in these mice revealed impaired CD4⁺ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT⁺FOXP3⁺ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT⁺FOXP3⁺ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT⁺FOXP3⁺ Treg cells can regulate intestinal immunity while leaving systemic responses intact.

环境肠道功能障碍（EED）是一种由营养不良和慢性感染引起的胃肠道炎症性疾病。EED 与儿童发育迟缓和口服疫苗效力降低有关。为了研究 EED 期间口服疫苗失败的机制，我们开发了一种微生物群和饮食依赖的小鼠 EED 模型。对这些小鼠中大肠杆菌不稳定毒素疫苗特异性 CD4 ⁺ T 细胞的分析显示，小肠中的 CD4 ⁺ T 细胞反应受损，但淋巴结中没有。EED 小鼠的小肠内 RORγT ⁺ FOXP3 ^{+频率增加}调节性 T (Treg) 细胞。从 Treg 细胞中靶向缺失 RORγT 可恢复小肠疫苗特异性 CD4 T 细胞反应和疫苗介导的攻击保护。然而，RORγT ⁺ FOXP3 ⁺ Treg 细胞的消融使小鼠更容易受到 EED 诱导的发育迟缓。我们的研究结果提供了对口服疫苗在 EED 中效果不佳的洞察，并强调了 RORγT ⁺ FOXP3 ⁺ Treg 细胞如何调节肠道免疫，同时保持全身反应完整。