T-cell help dependence of memory CD8+ T-cell expansion upon vaccinia virus challenge relies on CD40 signaling

Due to their capacity to differentiate into long-lived memory cells, CD8(+) T cells are able to resolve subsequent infections faster than during the primary response. Among other factors, CD4(+) T cells play a crucial role during primary and secondary CD8(+) T-cell responses. However, the timing and mechanisms by which they influence CD8(+) T cells may differ in primary and secondary responses. Here, we demonstrate that during both primary and secondary vaccinia virus infection, CD4(+) T cells are necessary to promote CD8(+) T-cell responses. While CD4(+) T cells contributed to memory CD8(+) T-cell development, they were even more important during memory recall responses during challenge, as absence of CD4(+) T cells during challenge resulted in markedly decreased proliferation and increased apoptosis. T-cell help during primary and secondary responses was mediated via CD40 signaling, with DCs being an integral part of that pathway. As opposed to primary CD8(+) T-cell responses where only a combination of agonistic CD40 signaling and provision of IL-2 could substitute for T-cell help, agonistic CD40 triggering alone was sufficient to rescue memory CD8(+) T-cell responses in absence of T-cell help in the context of vaccinia virus infection.