Recognition of microbial viability via TLR8 drives TFHcell differentiation and vaccine responses

Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (TFHcell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting TFHcell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust TFHcell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of TFHcell differentiation and a promising target for TFHcell–skewing vaccine adjuvants.