Innate Immunity and Adenovirus Vector Immunization

Abstract

Innate immunity plays a critical role as an initial barrier to infection. In addition, innate immunity can serve to shape and regulate adaptive immune responses. Therefore, investigating the integration of innate and adaptive immunity is important for understanding adaptive immune phenotypes elicited by vaccination. As part of the innate immune defense system, natural killer (NK) cells have a multifunctional role as they can eliminate infected cells and serve as regulators of the immune response. Prior studies have shown that NK cells can regulate T cell responses, T cell phenotypes, and pathological outcomes. Here we use a lymphocytic choriomeningitis virus (LCMV) infection model to show that antigen-specific T cell responses in adenovirus serotype 5 (Ad5) vector vaccinated animals are less sensitive to NK cell rheostat function in contrast to unvaccinated animals following challenge with LCMV clone-13. Further, while high levels of functional virus-elicited CD8+ T cell responses can lead to the development of immunopathology in the absence of NK cells in unvaccinated animals, higher levels of Ad5 vaccine-elicited CD8+ T cells are beneficial and protective. This overall suggests that while NK cells can regulate virus-elicited T cells, Ad5 vaccine-elicited T cells may be less amenable to NK cell regulation. In a broader context, we surveyed the induction and evolution of innate immune responses following immunization. Innate immune stimulation results in the production of cytokines and chemokines by various immune cell populations. We show that innate immune responses are initiated almost immediately following intramuscular Ad vector immunization. The cytokine and chemokine signatures suggest broad innate immune activation and mobilization of immune cell subsets with the first 72 hours following immunization. These data highlight that the innate immune response following immunization with replication-incompetent adenovirus vectors is initiated rapidly and is largely transient. Together, these data contribute to our understanding of innate immunity following Ad vector vaccination and implications for adaptive immunity. Thus, investigation into the role of innate immunity in shaping and regulating vaccine-elicited adaptive immune responses is critical for a mechanistic understanding of vaccine immunology, and for the optimal design of vaccine regimens for challenging diseases.