Antigen presentation by lung epithelial cells directs CD4+ TRM cell function and regulates barrier immunity

Anukul T Shenoy,Anne Hinds,Alicia M Soucy,Aditya Ramanujan,Thomas Braun,Carolina Lyon De Ana,Neelou S Etesami,Isabelle Salwig,Ian M C Martin,Filiz T Korkmaz,Anna C Belkina,Joseph P Mizgerd,Emad I Arafa,Hasmeena Kathuria,Lee J Quinton,Matthew R Jones,Wesley N Goltry,Kimberly A Barker,Brian R Tilton

doi:10.1038/s41467-021-26045-w

Abstract

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

Highlights

Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells
The surfactant protein C (SPC)-GFPlow cells coexpressed markers characteristic of Alveolar type 2 (AT2) cells (Spc) and club cells (Scgb1a1), but not markers for multiciliated cells (Foxj1) or Alveolar type 1 (AT1) cells (Aqp5) (Fig. 1f). To further characterize this lung epithelial cells (LECs) type, we used bronchioalveolar stem cell (BASC) reporter mice that express YFP and mCherry inserted into Spc and Scgb1a1 loci, respectively[21] (Fig. 1g). These mice confirmed a population of SPClow cells with high levels of MHC-II, and revealed that they were distinguishable from club cells (SCGB1A1high) that were MHC-IIlow, bronchioalveolar stem cells[22] (BASC; SCGB1A1medium SPCmedium) that were MHC-IImedium, and AT2 cells (SPChigh) that were MHC-IIhigh (Fig. 1g)
We show that diverse LECs, including a distinct SPClowMHChigh LEC, function as antigen-presenting cells (APC) to CD4+ T cells in anatomically segregated fashions (Supplementary Figure 19a)

Summary

Introduction

Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. TRM cell formation and responses depend on diverse natures of antigenic stimuli, types of antigen-presenting cells (APC), and costimulatory signals and cytokines within the challenged tissue[3,4] These signals diversify TRM cell responses beyond their initial phenotype specification, yielding T cell plasticity that enhances anti-microbial immunity and tissue barrier integrity[3,5,6]. The only known function of MHC-II is antigen presentation to CD4+ T cells, whether barrier epithelial cells direct CD4+ TRM cell activities during exposures to relevant cognate antigens remains speculative. We postulate that lung epithelial cells (LECs) mediate antigen presentation to pulmonary CD4+ TRM cells in order to regulate their localization and activities after Spn infection. We define molecular factors involved in this communication axis and show a physiological role of LEC MHC-II related to CD4+ TRM cell plasticity and immunity

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