Recognition of microbial viability via TLR8 promotes T follicular helper cell differentiation and vaccine responses

Live attenuated vaccines are generally highly efficacious and 30 often superior to inactivated vaccines, yet the underlying mechanisms remain largely unclear. Here we identify innate immune recognition of microbial viability as a potent stimulus for T follicular helper (TFH) cell differentiation and vaccine responses. Antigen presenting cells (APC) distinguish viable from dead bacteria through the detection of bacterial RNA via Toll-like receptor (TLR)-8. Live bacteria, bacterial RNA, or synthetic TLR8 agonists induce a specific cytokine profile in human and porcine APC and promote TFH cell differentiation, which dead bacteria and other TLR ligands fail to induce. Accordingly, vaccination with live, but not heat killed attenuated bacteria induces TFH cell differentiation and robust humoral immune responses in swine. A hypermorphic TLR8 polymorphism was associated with enhanced protective immunity elicited by a live bacterial vaccine against tuberculosis in a human cohort. We provide mechanistic insights into the superiority of live vaccines and we identify TLR8 as a key regulator of TFH cell differentiation and a promising target for TFH-skewing adjuvants.