Development of anti-viral CD8+ T cell memory in the respiratory environment

Abstract

Mucosal surfaces represent the major portal by which pathogens enter the body, yet there is limited understanding of how CD8+ T cell responses develop and are maintained at these sites. The majority of knowledge on CD8+ T cell responses and memory formation has been amassed in models of acute, systemic infections, even though it is appreciated that mucosal sites consist of immunological environments unique from sites in which responses to systemic infections develop. Moreover, a firm understanding of how memory is generated in mucosal sites is important for the development of vaccines, which may employ a systemic or mucosal route of immunization, such as those directed against influenza virus. Vaccines that target protective CD8+ T cell responses are of particular interest for influenza, as memory CD8+ T cells can limit severe disease and can offer protection against multiple influenza subtypes. This study shows that the respiratory environment can directly influence CD8+ cell responses, resulting in localized changes in CD8+ T cell memory formation as well as broadly inhibiting the formation of long-lived memory cells. We show that the mucosal cytokine thymic stromal lymphopoietin (TSLP) is produced early following mucosal influenza infection, and acts on CD8+ effector cells in a direct and non-redundant way, promoting the proliferation of these cells at the site of infection. This early response influences memory development resulting in more of an effector memory population of cells. I go on to show that by comparing vesicular stomatitis virus infection delivered by the intranasal or intravenous route, that the respiratory environment results in memory CD8+ T cell population that is skewed from the archetypical memory developmental programs defined in systemic models of infection, resulting in numerically deficient memory. Together this work suggests that the respiratory environment can uniquely transform CD8+ T responses towards a more short-lived population of cells, and that protective vaccination strategy will require thoughtful modifications to bypass the restrictions conferred by the respiratory environment and promote memory development.