Antigen presentation by lung epithelial cells directs CD4(+) T(RM) cell function and regulates barrier immunity

Barrier tissues are populated by functionally plastic CD4(+) resident memory T (T(RM)) cells. Whether the barrier epithelium regulates CD4(+) T(RM) cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)(low)MHC(high) 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(RM) cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4(+) T(RM) 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(RM) cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4(+) T(RM) cell function and identify epithelial-CD4(+) T(RM) cell immune interactions as core elements of barrier immunity.