Systems immunology approaches demonstrate that CPS‐protected volunteers preferentially activate NFκB.112 NFκB signaling is required for the production of malaria‐protective cytokines including granzyme B and IFN‐γ, but could be inhibited by the high expression of CTLA‐4 and TIM‐3 on slow responder T cells. This evidence concerns the gene CTLA4 and malaria.