CD4 T Cells Regulate Adenovirus Vector-Elicited Cellular and Humoral Immune Responses

Abstract

The processes that regulate viral vector vaccine-elicited cellular and humoral immune responses remain poorly defined. Thus, in this thesis, the role of CD4+ T cells – master regulators of adaptive immunity – in modulating adenovirus (Ad) vector-elicited cytotoxic CD8+ T cell responses and transgene-specific antibody responses was investigated. CD4+ T cell help is critical for the induction of CD8+ T cell and antibody responses, but the mechanisms and timing of help to each of these two arms of the immune system are distinct. CD4+ T cell help is required immediately and continuously for one week to drive functional CD8+ T cell effector differentiation and prevent dysfunction. Elevated signaling via PD-1, decreased IL-2 signaling, and increased non-canonical NFAT signaling all appear important for driving this CD8+ T cell dysfunction and impairing effector functionality. Absence of CD4+ T cells at the time of Ad vector immunization prevents the development of antigen-specific antibody responses. However, if the CD4+ T cell population is allowed to recover then fully functional antigen-specific antibody responses develop without the re-administration of antigen. Thus, CD4+ T cell help is absolutely required for the development of antibody responses following Ad vector immunization, but, intriguingly, help can be provided at a time separate from initial antigen exposure. Collectively, CD4+ T cell help and the appropriate timing of this help are critical for the generation of optimal CD8+ T cell and antibody responses following Ad vector immunization. These data advance our understanding of how CD4+ T cells regulate Ad vector-elicited cellular and humoral immune responses, and may improve rational vaccine design.