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<sub>H</sub> cells. A clearer understanding of the contribution of T<sub>H</sub> cells to CTL development has been hampered by the fact that most T<sub>H</sub>-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T<sub>H</sub>-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T<sub>H</sub>-dependent and T<sub>H</sub>-independent CTLs and find in both cases that CD4<sup>+</sup> T cells are dispensable for primary expansion of CD8<sup>+</sup> 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<sub>H</sub> 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.