Antigen presentation by lung epithelial cells directs CD4+ TRM 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)^lowMHC^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. The maintenance of T resident memory (T_RM) cells within pulmonary tissues is incompletely understood. Here the authors show that antigen presentation by lung epithelial cells maintains function and phenotype of pulmonary T_RM cells within specific locational niches. [ABSTRACT FROM AUTHOR]