Antigen presentation by lung epithelial cells directs CD4 T cell function and regulates barrier immunity.

Barrier tissues are populated by functionally plastic CD4 resident memory T (T) cells. Whether the barrier epithelium regulates CD4 T cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)MHC epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4 T cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4 T cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4 T cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4 T cell function and identify epithelial-CD4 T cell immune interactions as core elements of barrier immunity.