Some of the most successful vaccines to date, including those against the deadly viruses small pox, measles, mumps, and rubella, comprise attenuated viral particles, capable of inducing both humoral and cellular immunity. However, because protection through live infection is not feasible for many pathogens, including HIV, malaria, tuberculosis, and cancer, alternative vaccine approaches are needed. A single immunization with a protein subunit antigen and a combination of agonists toward pattern recognition receptors and CD40 (combined-adjuvant subunit vaccine) generates a magnitude of CD8+ and CD4+ T cell responses that is exponentially larger than those typically induced by viral vectors in both mice and non-human primates. Given the clinical promise of this vaccine platform, the careful study of the mechanisms controlling its potency may uncover novel targets for the development of more effective prophylactic and therapeutic vaccines. Over the past decade, studies of immunization and infection have revealed shared and distinct pathways utilized in the generation of immunological memory. We have documented a unique metabolic program used by expanding vaccine-elicited T cells, and requirements for cytokines (IL-15, IL-27) and transcription factors (Tbet, Eomes) that are dispensable for the expansion of infection-elicited T cells. These discrepancies led us to question other factors previously thought to be unimportant for the generation of CD8+ T cell responses, such as the concurrent activation and proliferation of antigen-specific B cells. Given the disproportionate expansion of B cells very early following subunit immunization, it seemed plausible that B cells could provide costimulatory support for the ensuing CD8+ T cell response, either directly, or indirectly. Preliminary data support this unconventional proposition. In fact, preliminary data also show that CD8+ T cell responses likewise benefit the antibody response to subunit vaccination. We do not yet understand the underlying mechanisms that integrate B cells and CD8+ T cells for the generation of long-lived cellular and humoral immunity. Our proposal will use classic immunological approaches to fully elucidate, specific to the context of subunit vaccination, 1) the role of B cell antigen presentation and cytokine production in the regulation of CD8+ T cell survival and cell fate determination, 2) the role of B cells in CD8+ T cell memory formation and maintenance, and 3) the mechanisms by which antigen- specific CD8+ T cells influence B cell activation and antibody formation.
After a single immunization, our vaccine produces the most potent cellular immune response yet observed of any non-infectious vaccine, capable of protecting against infectious challenge even in mice whose immune system is compromised. In the process of investigating this and other vaccination strategies, we made the surprising discovery that CD8+ T cell responses to subunit vaccines require the participation of antigen-specific B cells, and, just as surprisingly, that maximal B cell responses also depend upon CD8+ T cells. We believe the development of more effective prophylactic and therapeutic vaccines will benefit from the proposed careful dissection of the mechanisms responsible for this previously unidentified, mutually beneficial collaboration between cellular and humor immunity.
