Abstract
Abstract Tissue-resident memory T (T RM) cells are poised at mucosal sites to confer robust protection against secondary infection. In contrast to skin and intestine, lung T RMcells are short lived with a decline in number coinciding with a decline in protective immunity against subsequent heterosubtypic influenza infections. Despite this causal relationship, the localization, dynamics and function of lung Trm during secondary responses remains poorly defined. To address this, we used two-photon intravital microscopy of lungs to assess in real time the spatiotemporal dynamics of lung T RMcells during recall infection. At a memory time point, lung T RMcells (representing both CD103 +and CD103 −subsets) exhibit significantly lower motility and less displacement compared to an CD8 +effector T cells at an earlier time point post infection. Depletion of circulating CD8 +T cells using a low dose antibody administered systemically led to enrichment of lung T RMcells that exhibited slow to moderate speed scanning patterns. A fate mapping model for CD103 +T RMcells specifically revealed limited speed (<5 um/min) and patrolling behavior compared to CD103 −T RMcells. Within 24 hr of rechallenge, CD103 +T RMcells co-localized with infected cells and by 48 hr, lung-resident CD8 +T cells exhibit significantly lower motility with recruitment and clustering in infected regions in an antigen-specific manner. Protective immune responses by lung T RMcells is further accompanied by CXCR3-dependent migration of dendritic cells to draining lymph nodes as well as recruitment of inflammatory monocytes. Overall, these data unravel the spatiotemporal dynamics of lung T RMcells and interactions with recruited immune cells for early protective immunity. Supported by grants from NIH (GM134880, AI42767, AI114543, AI151183, AI167249, the Holden Cancer Center at the University of Iowa and its National Cancer Institute Award P30CA086862
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