Identification of distinct cDC2 subpopulations that direct microbiota-specific T cell differentiation

How the complex network of intestinal antigen presenting cells (APCs) instructs CD4⁺ T cell responses against the microbiota remains unclear. Here, we use Labeling Immune Partnerships by SorTagging Intercellular Contacts (LIPSTIC) to characterize the APCs that prime CD4⁺ T cells recognizing the commensal bacterium Akkermansia muciniphila. A. muciniphila-specific T cells engaged multiple transcriptionally distinct migratory cDC2 subpopulations, both at homeostasis, when A. muciniphila promotes T_FH differentiation, and during inflammation, when it also drives T_H1 and T_H17 differentiation. The identity of these subpopulations was unchanged by inflammation; however, the distribution of presentation across the subpopulations shifted, with increased presentation by inflammatory cDC2s favoring T_H1 and T_H17 polarization. These results reveal how distinct T cell differentiation trajectories can be determined through varied interactions with multiple, functionally distinct subpopulations of APCs.