T follicular helper (TFH) and Cytotoxic CD4 (ThCTL) are tissue-restricted CD4 effector subsets, functionally specialized to mediate optimal Ab production and cytotoxicity of infected cells. Influenza infection generates robust CD4 responses, including lung ThCTL and SLO TFH, that protect against reinfection by variant strains. Antigen (Ag) presentation after infection, lasts through the effector phase of the response. Here, we show that this effector phase Ag presentation, well after priming, is required to drive CD4 effectors to ThCTL and TFH. Using in vivo influenza models, we varied Ag presentation to effectors acutely, just at the effector phase. Ag presentation was required in the tissue of effector residence. We suggest these requirements contain unnecessary or potentially pathogenic CD4 responses, only allowing them if infection is uncleared. The results imply that providing effector phase Ag, would lead to stronger humoral and CD4 tissue immunity and thus can be applied to improve vaccine design
