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. muciniphil a promotes T _FH differentiation, and during inflammation, when it also drives T _H 1 and T _H 17 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 _H 1 and T _H 17 polarization. These results reveal how distinct T cell differentiation trajectories can be determined through varied interactions with multiple, functionally distinct subpopulations of APCs.