CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes

A long-standing paradox in cellular immunology concerns the conditional requirement for CD4(+) T-helper (T-H) cells in the priming of cytotoxic CD8(+) T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4(+) T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T-H cells(1-4). A clearer understanding of the contribution of T-H cells to CTL development has been hampered by the fact that most T-H-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T-H-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T-H-dependent and T-H-independent CTLs and find in both cases that CD4(+) T cells are dispensable for primary expansion of CD8(+) T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T-H cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8(+) T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.