CD4 T cell interactions with gut antigens

How the immune system interacts with distinct classes of intestinal antigens remains unknown. Here, we hierarchically classified self-, diet-, or microbiota-dependent CD4 T cell receptors (TCRs) by controlling exposure to dietary antigens and microbes. Unlike prior studies, this macro-immunologic analysis revealed that diet-dependent regulatory T (Treg) TCRs were a minority in the small intestine (SI) and equally found in the colon. Interestingly, Treg and effector TCRs differed, being driven by self, microbes, and diet; versus almost exclusively by microbes, respectively. Micro-immunologic analysis of individual TCRs showed complex bi-directional interactions between diet and microbiota. This was also seen with switching to antigen-free diet, akin to its use for human inflammatory bowel disease, which decreased colitis in part due to loss of microbial, and notably, dietary, effector T cell responses. Thus, deconvoluting the gut immune interactome may facilitate identifying primary microbial and dietary drivers of T cell responses during health and disease.