CD4+ T cell help is critical for optimal CD8+ T cell expansion after priming in many experimental
systems. However, a role for CD4+ T cells in regulating the initial steps of CD8+ T cell effector
differentiation is not well established. Here we demonstrate that absence of CD4+ T cells at the
time of replication-incompetent adenovirus vector immunization of C57BL/6 mice led to
immediate CD8+ T cell dysfunction that was phenotypically, functionally, and transcriptionally
characteristic of exhaustion at the first detectable timepoints. This dysfunctional state was
imprinted within 3 days of immunization and could not be reversed by provision of CD4+ T cell
help after priming. Partial rescue of unhelped CD8+ T cell expansion and effector differentiation
could be achieved by PD-1 pathway blockade or recombinant IL-2 administration. This study
identifies a novel, previously undescribed role of CD4+ T cells to prevent immediate
dysfunction and features of exhaustion in CD8+ T cells following antigen priming.