Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Abstract

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 (T 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 T cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust T 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-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of T cell differentiation and a promising target for T cell-skewing vaccine adjuvants.

Agonist and antagonist ligands of toll-like receptors 7 and 8: Ingenious tools for therapeutic purposes

“…TLRs 7 and 8 are implicated in the recognition of naturally derived uridineerich ssRNAs of influenza and HIV [36]. In addition TLR7 and TLR8 recognize bacterial RNA [51,64]. Furthermore, TLR7 and 8 are expressed in human plasmacytoid DCs (pDCs), in T and B cells, monocytes and macrophages [65,66].…”

“…Recently, Zhang et al identified, for the first time, human TLR8 small antagonist molecules with a novel inhibition mechanism [304]. SAR studies on the pyrazolo[1,5-a]pyrimidine series led to identification of the compound: CU-CPT8m (64), which proved to be the most active with an IC50 of 67 nM and a strong ability to inhibit the production of pro-inflammatory cytokines (Fig. 34).…”

Extracellular RNA Sensing by Pattern Recognition Receptors

“…Unlike TLR7, TLR8 activation mainly results in the production of inflammatory cytokines due to the types of cells in which it is expressed. A recent study demonstrated that recognition of live bacteria by TLR8 induced human monocytes to produce large amounts of IL-12, which drives a follicular helper T-cell response in naive human CD4 + T cells [85]. …”

Distinguishing naive‐ from memory‐derived human B cells during acute responses

“…Others show that IL‐1β, produced by monocytes downstream of TLR signalling and inflammasome activation, induces differentiation of T follicular helper cells, which augment antibody production . Moreover, Ugolini et al . demonstrate that TLR8 engagement represents a mechanism via which CD14 + CD16 + monocytes selectively detect viable as opposed to dead microorganisms, and signal this via producing IL‐1β, which activates T follicular helper cells.…”

“…Others show that IL-1b, produced by monocytes downstream of TLR signalling and inflammasome activation, induces differentiation of T follicular helper cells, which augment antibody production. 37 Moreover, Ugolini et al 38 demonstrate that TLR8 engagement represents a mechanism via which CD14 + CD16 + monocytes selectively detect viable as opposed to dead microorganisms, and signal this via producing IL-1b, which activates T follicular helper cells. Similarly, Kwissa et al 21 found that CD14 + CD16 + monocytes, which are induced by dengue virus infection, and by R848 but not CpG, enhance B-cell differentiation, providing another possible explanation for the differential role of monocytes in R848-versus CpG-stimulated B-cell differentiation.…”