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

Beng San Yeoh,Andrew T Gewirtz,Matam Vijay-Kumar

doi:10.3389/fcimb.2019.00029

Abstract

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.

Highlights

The microbial biomass in the intestine is enriched with diverse microbial-associated molecular patterns (MAMPs) that are recognizable by host pathogen recognition receptors (PRRs)
We extend this study to examine the efficacy of anti-FliC Ab against enteric and systemic infection by Salmonella typhimurium
While MAMPs have been shown to induce immune tolerance in vitro (Medvedev et al, 2000; Mizel and Snipes, 2002; Otte et al, 2004; Sun et al, 2007; Li et al, 2012), the occurrence of tolerance is relatively under-studied in vivo (De Vos et al, 2009)

Summary

Introduction

The microbial biomass in the intestine is enriched with diverse microbial-associated molecular patterns (MAMPs) that are recognizable by host pathogen recognition receptors (PRRs). To deter unwarranted inflammatory responses, the host has evolved built-in mechanisms to promote immunotolerance against repeated exposure to MAMPs (Rakoff-Nahoum et al, 2004) These mechanisms include strategic expression of PRRs (e.g., TLR5) on the basolateral side of the epithelia (Gewirtz et al, 2001a), downregulation of surface PRRs (e.g., TLR2, TLR4, MD-2, TLR5) (Medvedev et al, 2000; Abreu et al, 2001; Otte et al, 2004), and secretion of endogenous inhibitors [e.g., soluble CD14, secretory IL-1 receptor antagonist (sIL1Ra), soluble TNF receptor I and II] (Liew et al, 2005). LPS pre-treatment could regulate TLR5 responses to FliC in vitro, though the magnitude of such “cross-tolerance” depends on the doses and cell-type studied (Mizel and Snipes, 2002; Sun et al, 2007; Li et al, 2012)

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