CD4⁺ T cell help creates memory CD8⁺ T cells with innate and help-independent recall capacities.

CD4⁺ T cell help is required for the generation of CD8⁺ cytotoxic T lymphocyte (CTL) memory. Here, we use genome-wide analyses to show how CD4⁺ T cell help delivered during priming promotes memory differentiation of CTLs. Help signals enhance IL-15-dependent maintenance of central memory T (T_CM) cells. More importantly, help signals regulate the size and function of the effector memory T (T_EM) cell pool. Helped T_EM cells produce Granzyme B and IFNγ upon antigen-independent, innate-like recall by IL-12 and IL-18. In addition, helped memory CTLs express the effector program characteristic of helped primary CTLs upon recall with MHC class I-restricted antigens, likely due to epigenetic imprinting and sustained mRNA expression of effector genes. Our data thus indicate that during priming, CD4⁺ T cell help optimizes CTL memory by creating T_EM cells with innate and help-independent antigen-specific recall capacities.