Immediate dysfunction of vaccine-elicited CD8⁺ T cells primed in the absence of CD4⁺ T cells

CD4⁺ T cell help is critical for optimal CD8⁺ T cell memory differentiation and maintenance in many experimental systems. In addition, many reports have identified reduced primary CD8⁺ T cell responses in the absence of CD4⁺ T cell help, which often coincides with reduced Ag or pathogen clearance. In this study, we demonstrate that absence of CD4⁺ T cells at the time of adenovirus vector immunization of mice led to immediate impairments in early CD8⁺ T cell functionality and differentiation. Unhelped CD8⁺ T cells exhibited a reduced effector phenotype, decreased ex vivo cytotoxicity, and decreased capacity to produce cytokines. This dysfunctional state was imprinted within 3 d of immunization. Unhelped CD8⁺ T cells expressed elevated levels of inhibitory receptors and exhibited transcriptomic exhaustion and anergy profiles by gene set enrichment analysis. Dysfunctional, impaired effector differentiation also occurred following immunization of CD4⁺ T cell-deficient mice with a poxvirus vector. This study demonstrates that following priming with viral vectors, CD4⁺ T cell help is required to promote both the expansion and acquisition of effector functions by CD8⁺ T cells, which is accomplished by preventing immediate dysfunction.