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 (TFH cell) 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 TFH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust TFH cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guerin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of TFH cell differentiation and a promising target for TFH cell-skewing vaccine adjuvants.
- Ugolini, M.
- Gerhard, J.
- Burkert, S.
- Jensen, K. J.
- Georg, P.
- Ebner, F.
- Volkers, S. M.
- Thada, S.
- Dietert, K.
- Bauer, L.
- Schafer, A.
- Helbig, E. T.
- Opitz, B.
- Kurth, F.
- Sur, S.
- Dittrich, N.
- Gaddam, S.
- Conrad, M. L.
- Benn, C. S.
- Blohm, U.
- Gruber, A. D.
- Hutloff, A.
- Hartmann, S.
- Boekschoten, M. V.
- Muller, M.
- Jungersen, G.
- Schumann, R. R.
- Suttorp, N.
- Sander, L. E.
Keywords
- Adult
- Animals
- Antibody Formation/immunology
- Cell Differentiation/immunology
- Female
- Humans
- Lymphocyte Activation/*immunology
- Male
- Microbial Viability/*immunology
- Swine
- T-Lymphocytes, Helper-Inducer/*immunology
- Toll-Like Receptor 8/*immunology
- Vaccines, Attenuated/*immunology