First come, first served: Tissue resident memory T cells (TRM) generated to an initial infection alter the magnitude, phenotype, and localization of TRM to unrelated pathogens 2947

Abstract Description Tissue-resident memory T cells (TRM) provide regionalized immunity through potent effector responses and optimal localization in tissues. While mouse models have offered significant insights into TRM against single or heterosubtypic infection, they fail to recapitulate the complexity of human tissue exposed to a lifetime of antigens. Here, we developed a mouse model to track Ag-specific TRM each independently responding to sequentially administered respiratory virus, enabling examination of how pre-existing TRM impact newly-recruited populations, and vice-versa. Although prior exposure to IAV (X31) infection did not hinder the effector response to IBV, establishment of memory was impaired. Notably, lung IBV-specific CD4 T cells shifted from a CD69+CXCR6+ TRM phenotype after single infection, to CXCR6-FR4+ Tfh-like cells in previously infected mice, localizing away from airway epithelia toward B cell clusters. However, depleting the original IAV-specific T cells restored the IBV-specific TRM response in double infected mice to that of a single IBV infection. Finally, IBV infection followed by X31 priming and PR8 rechallenge elicited greater morbidity than heterosubtypically rechallenged mice without a prior infection, suggesting competition alters TRM phenotype, localization, and protective capacity. Our data highlight the impact of our immunological past on future T cell responses, and the importance of our formative exposures in establishing an optimally protective niche. Funding Sources NIH AI150680 Topic Categories Mucosal and Regional Immunology (MUC)