Innate Immune Recognition of Bacterial Viability Instructs Human T follicular Helper Cell Differentiation

Live attenuated vaccines are often superior to dead vaccines, yet the immunological mechanisms remain largely obscure. We have recently uncovered an inherent capacity of antigen-presenting cells (APC) to discriminate live from killed bacteria by virtue of vita-PAMPs. Here we found that innate recognition of bacterial viability strongly promotes the differentiation of fully functional T follicular helper (TFH) cells. We identify TLR8 and its signaling adaptor MyD88 as critical sensor for bacterial viability in human APC, activation of which is required and sufficient to induce selective transcriptional remodeling and the production of TFH promoting signals like IL-12. Activators of other TLRs including licensed vaccine adjuvants fail to do so. Consequently, vita-PAMP receptors such as TLR8 represent promising targets for adjuvants to improve the efficacy of modern inanimate subunit vaccines. Human monocytes were infected with live or heat-killed E. coli for 6h.