Lung CD4+ resident memory T cells remodel epithelial responses to accelerate neutrophil recruitment during pneumonia


Previous pneumococcal experience establishes lung-resident IL-17A-producing CD4+ memory TRM cells that accelerate neutrophil recruitment against heterotypic pneumococci. Herein, we unravel a novel crosstalk between CD4+ TRM cells and lung epithelial cells underlying this protective immunity. Depletion of CD4+ cells in pneumococcus-experienced mice diminished CXCL5 (but not CXCL1 or CXCL2) and downstream neutrophil accumulation in the lungs. Epithelial cells from experienced lungs exhibited elevated mRNA for CXCL5 but not other epithelial products such as GM-CSF or CCL20, suggesting a skewing by CD4+ TRM cells. Genome-wide expression analyses revealed a significant remodeling of the epithelial transcriptome of infected lungs due to infection history, ~80% of which was CD4+ cell-dependent. The CD4+ TRM cell product IL-17A stabilized CXCL5 but not GM-CSF or CCL20 mRNA in cultured lung epithelial cells, implicating posttranscriptional regulation as a mechanism for altered epithelial responses. These results suggest that epithelial cells in experienced lungs are effectively different, owing to their communication with TRM cells. Our study highlights the role of tissue-resident adaptive immune cells in fine-tuning epithelial functions to hasten innate immune responses and optimize defense in experienced lungs, a concept that may apply broadly to mucosal immunology.

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We thank the BU Flow Cytometry Core Facility and Dr. Patrick Autissier for expert technical assistance and Adam Gower for bioinformatics guidance and consultation. This work was supported by the NIH including R35 HL135756 and R01 AI115053 (to J.P.M.); F31-HL127978 (to G.A.W.); R01 HL104053 (to M.R.J.); R01 GM120060 and R01 HL111459 (to L.J.Q.); and NIH T32 HL007035 and T32 AI089673 (for support of trainees).

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G.A.W. and A.T.S. executed experiments. E.I.A., A.K.W., N.M.S.S. and I.M.C.M. provided experimental assistance. G.A.W., A.T.S. and J.P.M. designed experiments and analyzed data. M.R.J., L.J.Q. and J.P.M. provided reagents and resources. A.T.S. and J.P.M. wrote original draft of the manuscript and all co-authors reviewed and edited the manuscript.

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Correspondence to Joseph P. Mizgerd.

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Co-authors: Anukul T. Shenoy, Gregory A. Wasserman

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Shenoy, A.T., Wasserman, G.A., Arafa, E.I. et al. Lung CD4+ resident memory T cells remodel epithelial responses to accelerate neutrophil recruitment during pneumonia. Mucosal Immunol 13, 334–343 (2020).

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