Enteropathy-induced regulatory T cells inhibit intestinal CD4+ T cell responses against oral vaccines

Summary Environmental Enteric Dysfunction (EED) is an intestinal disease caused by malnutrition and infection that leads to malabsorption and stunting. EED is also associated with a reduced efficacy of oral vaccines. We show in a microbiota and diet-dependent model of EED that oral vaccine-specific CD4 + T cell responses fail in the small intestine but responses in the draining lymph node were unaffected. Accordingly, the number of immunosuppressive RORγT + FOXP3 + T regs in the small intestine inversely correlated with the response to oral vaccination. Depletion of RORγT + FOXP3 + T regs indicated that they were necessary for EED-associated inhibition of the vaccine response. Additionally, RORγT + FOXP3 + T regs are important to regulate EED-associated inflammation as their depletion significantly worsened stunting. We have shown that EED-associated intestinal inflammation leads to a localized intestinal blockade of CD4 T cell immunity. These results support a modular model for immunity where tissue responses can be regulated independently of systemic immunity to prevent autoinflammation.