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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Quinton, L. J., Walkey, A. J. & Mizgerd, J. P. Integrative physiology of pneumonia. Physiol. Rev. 98, 1417–1464 (2018).
(WHO) WHO. The Top 10 Causes of Death (World Health Organization, Geneva, 2014).
Collaborators GBDCoD. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1736–1788 (2018).
Bogaert, D., De Groot, R. & Hermans, P. W. Streptococcus pneumoniae colonisation: the key to pneumococcal disease. Lancet Infect. Dis. 4, 144–154 (2004).
Mizgerd, J. P. Respiratory infection and the impact of pulmonary immunity on lung health and disease. Am. J. Respir. Crit. Care Med. 186, 824–829 (2012).
Curns, A. T., Holman, R. C., Sejvar, J. J., Owings, M. F. & Schonberger, L. B. Infectious disease hospitalizations among older adults in the United States from 1990 through 2002. Arch. Intern. Med. 165, 2514–2520 (2005).
Black, R. E. et al. Global, regional, and national causes of child mortality in 2008: a systematic analysis. Lancet 375, 1969–1987 (2010).
Jain, S. et al. Community-acquired pneumonia requiring hospitalization among U.S. adults. N. Engl. J. Med 373, 415–427 (2015).
Jain, S. et al. Community-acquired pneumonia requiring hospitalization among U.S. children. N. Engl. J. Med. 372, 835–845 (2015).
Daniels, C. C., Rogers, P. D. & Shelton, C. M. A review of pneumococcal vaccines: current polysaccharide vaccine recommendations and future protein antigens. J. Pediatr. Pharm. Ther. 21, 27–35 (2016).
Shenoy A. T., Orihuela C. J. Anatomical site-specific contributions of pneumococcal virulence determinants. Pneumonia (Nathan) 8, pii: 7 (2016).
Quinton, L. J. & Mizgerd, J. P. Dynamics of lung defense in pneumonia: resistance, resilience, and remodeling. Annu. Rev. Physiol. 77, 407–430 (2015).
Yao, Y. et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175, 1634–1650 e1617 (2018).
Beura, L. K. et al. Normalizing the environment recapitulates adult human immune traits in laboratory mice. Nature 532, 512–516 (2016).
Thome, J. J. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).
Smith, N. M. et al. Regionally compartmentalized resident memory T cells mediate naturally acquired protection against pneumococcal pneumonia. Mucosal Immunol. 11, 220–235 (2018).
Teijaro, J. R. et al. Cutting edge: tissue-retentive lung memory CD4 T cells mediate optimal protection to respiratory virus infection. J. Immunol. 187, 5510–5514 (2011).
Schenkel, J. M. & Masopust, D. Tissue-resident memory T cells. Immunity 41, 886–897 (2014).
Rosato, P. C., Beura, L. K. & Masopust, D. Tissue resident memory T cells and viral immunity. Curr. Opin. Virol. 22, 44–50 (2017).
Turner, D. L. & Farber, D. L. Mucosal resident memory CD4 T cells in protection and immunopathology. Front. Immunol. 5, 331 (2014).
Allie, S. R. et al. The establishment of resident memory B cells in the lung requires local antigen encounter. Nat. Immunol. 20, 97–108 (2019).
Weaver, C. T., Elson, C. O., Fouser, L. A. & Kolls, J. K. The Th17 pathway and inflammatory diseases of the intestines, lungs, and skin. Annu. Rev. Pathol. 8, 477–512 (2013).
Ye, P. et al. Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J. Exp. Med. 194, 519–527 (2001).
Chen, K. et al. IL-17 receptor signaling in the lung epithelium is required for mucosal chemokine gradients and pulmonary host defense against K. pneumoniae. Cell Host Microbe 20, 596–605 (2016).
Yamamoto, K. et al. Roles of lung epithelium in neutrophil recruitment during pneumococcal pneumonia. Am. J. Respir. Cell Mol. Biol. 50, 253–262 (2014).
Kamata, H. et al. Epithelial cell-derived secreted and transmembrane 1a signals to activated neutrophils during pneumococcal pneumonia. Am. J. Respir. Cell Mol. Biol. 55, 407–418 (2016).
Kuleshov, M. V. et al. Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 44(W1), W90–W97 (2016).
Herjan, T. et al. HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization. J. Immunol. 191, 640–649 (2013).
Karlsen, J. R., Borregaard, N. & Cowland, J. B. Induction of neutrophil gelatinase-associated lipocalin expression by co-stimulation with interleukin-17 and tumor necrosis factor-alpha is controlled by IkappaB-zeta but neither by C/EBP-beta nor C/EBP-delta. J. Biol. Chem. 285, 14088–14100 (2010).
Amatya, N., Garg, A. V. & Gaffen, S. L. IL-17 signaling: the yin and the yang. Trends Immunol. 38, 310–322 (2017).
Liu, Y. et al. IL-17A and TNF-alpha exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J. Immunol. 186, 3197–3205 (2011).
Chowdhury, S., Dijkhuis, A., Steiert, S. & Lutter, R. IL-17 attenuates degradation of ARE-mRNAs by changing the cooperation between AU-binding proteins and microRNA16. PLoS Genet. 9, e1003747 (2013).
Nouailles, G. et al. CXCL5-secreting pulmonary epithelial cells drive destructive neutrophilic inflammation in tuberculosis. J. Clin. Invest. 124, 1268–1282 (2014).
Stegemann-Koniszewski S., et al. Alveolar type II epithelial cells contribute to the anti-influenza A virus response in the lung by integrating pathogen- and microenvironment-derived signals. MBio 7, pii: e00276-16 (2016).
Leiva-Juarez, M. M., Kolls, J. K. & Evans, S. E. Lung epithelial cells: therapeutically inducible effectors of antimicrobial defense. Mucosal Immunol. 11, 21–34 (2018).
Iwasaki, A., Foxman, E. F. & Molony, R. D. Early local immune defences in the respiratory tract. Nat. Rev. Immunol. 17, 7–20 (2017).
Sun, D. et al. Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nat. Immunol. 12, 853–860 (2011).
Shen, F., Ruddy, M. J., Plamondon, P. & Gaffen, S. L. Cytokines link osteoblasts and inflammation: microarray analysis of interleukin-17- and TNF-alpha-induced genes in bone cells. J. Leukoc. Biol. 77, 388–399 (2005).
Shen, F., Hu, Z., Goswami, J. & Gaffen, S. L. Identification of common transcriptional regulatory elements in interleukin-17 target genes. J. Biol. Chem. 281, 24138–24148 (2006).
Amezcua Vesely, M. C. et al. Effector TH17 cells give rise to long-lived TRM cells that are essential for an immediate response against bacterial infection. Cell 178, 1176–1188 e1115 (2019).
Irizarry, R. A. et al. Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4, 249–264 (2003).
Dai, M. et al. Evolving gene/transcript definitions significantly alter the interpretation of GeneChip data. Nucleic Acids Res 33, e175 (2005).
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).
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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). https://doi.org/10.1038/s41385-019-0229-2
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