Bacterial toxins influence tissue resident memory T cell formation in the lungs 2256485

Abstract Introduction Tissue-resident adaptive immunity is crucial for protection against diverse respiratory pathogens. Indeed, lung-resident memory CD4+ T (TRM) and B (BRM) cells that develop following Streptococcus pneumoniae (Spn) experience are cross-protective against different serotypes of Spn, identifying these cells as key vaccine targets. Despite their significance for human health, the cues that mediate anti-Spn CD4+ TRM cell formation are unclear. Whether human pathobionts like Spn can modulate establishment of tissue-resident CD4+ TRM cells using virulence factors is unexplored. Methods Using a mouse model that uncouples CD4+ TRM cell establishment in the lungs from their initial priming in the lymph nodes, we asked if expression of the Spn pore-forming toxin pneumolysin (Ply) alters the lung-resident adaptive immune landscape. Multispectral flow cytometry was used to analyze TRM cell formation at different timepoints post infection. Results To our surprise, we found that Ply supports, rather than evades, greater CD4+ and CD8+ TRM cell establishment in the lung. The adaptive immune composition of the systemic circulation remained similar independent of the toxin, suggesting a more lung-specific immunomodulation by Ply. We also find that pneumolysin promotes recruitment of CD4+ TRM cell precursors to the lung and aids their survival locally. Our ongoing studies are focused on elucidating the molecular mechanisms driving this enhanced recruitment and survival leading up to TRM establishment. Conclusion Our studies uncover an unexpected role for bacterial toxins in instructing TRM cell establishment within non-lymphoid tissues and have implications for development of the next generation CD4+ TRM cell-directed anti-bacterial vaccines. Funding Source NIH Topic Categories Mucosal and Regional Immunology (MUC)