Adaptive Immunity Induces Tolerance to Flagellin by Attenuating TLR5 and NLRC4-Mediated Innate Immune Responses

The host immune system is constantly exposed to diverse microbial ligands, including flagellin (FliC; a ligand for TLR5 and NLRC4) and lipopolysaccharide (LPS; a ligand for TLR4), which could induce immune tolerance to subsequent exposure. Herein, we investigated the extent to which FliC induces self-tolerance in vivo and the role of adaptive immunity in mediating such effect. Mice pre-treated with FliC displayed attenuated serum keratinocyte-derived chemokine (KC), interleukin (IL)-6 and IL-18 responses to secondary challenge of FliC. A negative correlation was observed between high anti-FliC titer and reduced KC, IL-6, and IL-18 responses upon FliC re-challenge in WT mice, but not Rag1KO mice, suggesting that adaptive immunity could tolerize TLR5 and NLRC4. However, administration of LPS during FliC pre-treatment impaired the generation of anti-FliC antibodies and resulted in a partial loss of self-tolerance to FliC re-challenge. These findings may be relevant in the context of bacterial infection, as we observed that anti-FliC response are protective against systemic infection by Salmonella typhimurium. Taken together, our study delineates a distinct co-operative and reciprocal interaction between the innate and adaptive arms of immunity in modulating their responses to a bacterial protein.