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Abstract

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.
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)(MHChigh)-M-low 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.