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.