Resident memory CD8 T cells patrol the lung and mediate early protective immunity

Abstract

Abstract In contrast to the long-lived nature of resident-memory CD8 T cells (Trms) residing in the skin or intestine, Trms located in the lung parenchyma wane and their loss coincides with the decline of protective immunity against subsequent heterosubtypic Influenza infections. We utilized intravital 2-photon microscopy of live mice to dissect the relative contribution and examine the real-time spatiotemporal dynamics of secondary CD8 T cell responses containing or lacking lung Trms. Early post-Influenza infection, the lung contained a mixture of phenotypically defined circulating and CD69+/CD103+ resident-memory transgenic P14 cells which exhibited heterogeneous motility patterns, comprised of both highly motile cells and those exhibiting a slow to moderate scanning pattern. The incorporation of IV exclusion during intravital imaging predominantly labeled highly dynamic cells, and largely spared slower CD103+ Trms in the lung parenchyma and surrounding airways. Conversely, the selective loss of this slow to moderate population was observed with either CD103 antibody-mediated depletion of early memory or at 6 months post infection, suggesting that CD103+ CD8 Trms exhibit slow to moderate motility dynamics in the lung at homeostasis. Importantly, upon secondary infection, hosts containing Trms exhibited a higher proportion of CD8 T cells with altered dynamics, more pronounced clustering around infected cells in the lung in an antigen-specific manner and provided superior early heterosubtypic protection compared to hosts containing only circulating memory. Overall, these data indicate that lung Trms exhibit slow to moderate motility patterns, rapidly respond to and mediate early immunity to subsequent infections in the lung.