CDS T cell responses are remarkably diverse and play vital roles in immune mediated viral control. Thus, there is a crucial need to decipher the developmental cues that drive the differentiation of phenotypically and functionally distinct CDS T cell subsets, define how these constituents cooperate to achieve infection control, and delineate the signals that help sustain these populations over time. Our proposal is based upon a series of recently published and preliminary findings that have advanced our understanding of the importance of intercellular adhesion molecule (ICAM)-I in determining the composition and properties of anti-viral CDS T cell responses. The experimental plan is designed to capitalize on these observations and generate novel fundamental insights into how and when ICAM-1 interactions configure the memory CDS T cell pool, and program protective efficacy. In addition, we will also determine whether tactically targeting ICAM-1 interactions improves immunity and viral control. Promisingly, we have shown that mitigating ICAM-1 interactions preserves anti-viral CDS T cells which usually succumb to exhaustion during chronic viral infections. Thus, our studies have the potential to impact the field by providing new fundamental information regarding how CDS T cell responses are regulated, as well as deliver proof of principle evidence that blocking ICAM-1 interactions is a viable strategy for augmenting immunity to acute, chronic, and bystander infections. This is especially significant as practical strategies to enhance responses by manipulating the anti-viral CDS T cell pool are limited. We also propose to integrate our ICAM-1 studies, showing the retention of effector-phenotype CDS T cells following infection, with our new discovery that IL-21 helps to maintain effector-memory CDS T cells. Given the ubiquitous roles of CDS T cells in anti-viral defense our studies may broadly impact the field by defining the principles that govern and configure the development of these responses. Significantly, they will decipher how ICAM-1 interactions skew the composition of the antiviral CDS T cell pool and whether this can be targeted to enhance immunity.
There is a critical need to develop better strategies to promote viral control and limit pathogenesis, that are ideally directed by an in-depth fundamental understanding of disease processes and host protection mechanisms. This project is designed to provide novel insights into the roles of adhesion molecules in antiviral defence that may broadly impact the field by identifying potential new therapeutic targets to improve immunity.