Stimulation of the Intracellular Bacterial Sensor NOD2 Programs Dendritic Cells to Promote Interleukin-17 Production in Human Memory T Cells

Abstract

How the development of antibacterial T helper 17 (Th17) cells is selectively promoted by antigen-presenting dendritic cells (DCs) is unclear. We showed that bacteria, but not viruses, primed human DCs to promote IL-17 production in memory Th cells through the nucleotide oligomerization domain 2 (NOD2)-ligand muramyldipeptide (MDP), a derivative of bacterial peptidoglycan. MDP enhanced obligate bacterial Toll-like receptor (TLR) agonist induction of IL-23 and IL-1, which promoted IL-17 expression in T cells. The role of NOD2 in this IL-23-IL-1-IL-17 axis could be confirmed in NOD2-deficient DCs, such as DCs from selected Crohn's disease patients. Thus, antibacterial Th17-mediated immunity in humans is orchestrated by DCs upon sensing bacterial NOD2-ligand MDP.

TLR2‐activated human langerhans cells promote Th17 polarization via IL‐1β, TGF‐β and IL‐23

“…In DC of Crohn's disease patients that are deficient for detection of intracellular PGN derivate and with a lack of sensing MDP, diminished IL-17 was detected [43]. In line with these results it was previously observed that Th17 phenotype could be induced by human monocytes stimulated by hyphae of C. albicans [25], compounds of which are discussed as TLR2 ligands.…”

Induction, function and regulation of IL‐17‐producing T cells

“…Experimental autoimmune disease in many animal models such as EAE, EAU and CIA is induced by immunization with autoantigen in the presence of CFA; this is likely to involve the activation of innate inflammatory cytokines that drive Th1 and Th17 cells. Indeed there is already evidence that pathogens or PAMPs can promote the production of inflammatory cytokines from monocytes and DC, which activate IL-17 production by T cells [14,38,64]. Stimulation of DC with TLR3, TLR4 and TLR9 ligands was found to induce MyD88-dependent production of cytokines that promoted differentiation of IL-17 producing CD4 1 T cells [41].…”

“…38: 2636Immunol. -2649 Th17 cells in response to IL-23 stimulation in vitro [22,38]. Conversely, it was demonstrated that IL-23 could expand a population of IL-17-producing T cells from memory CD4 1 T cells in vitro [37] and IL-23-driven IL-17 secreting cells were pathogenic in EAE [22].…”

“…An independent study reported that IL-1b and IL-6 induced differentiation of naïve human T cells into Th17 cells following co-stimulation with anti-CD3 and anti-CD28 in vitro [51]. These studies found that, unlike murine T cells, human naïve T cells did not differentiate into IL-17-secreting T cells in response to TGF-b and IL-6 in vitro [38,50,52,53]. Furthermore, in a study of patients with genetic traits affecting TGF-b, IL-1, IL-6 and IL-23 production, enhanced TGF-b responses, due to mutations in TGFB1 and TGFBR2, did not alter expression of Th17 cells, whereas mutations in STAT3 and IL-12RB1 impaired dedifferentiation or expansion of Th17 cells in vivo [54].…”

The inflammasomes in health and disease: from genetics to molecular mechanisms of autoinflammation and beyond

“…79 IL-1b plays an important role in activating and sustaining the Th17-mediated response, especially in humans. [107][108][109][110] Considering the central role of Th17 cells in autoimmune diseases including rheumatoid arthritis (RA) and psoriasis, mutations in inflammasome-encoding genes may result in a broad spectrum of Th17 cell-mediated autoimmune disorders, through deregulation of IL-1b secretion. 107,[111][112][113][114][115][116] Genetic variants in several inflammatory genes, including NLRP3, are associated with two forms of autoimmune arthritis: juvenile idiopathic arthritis and RA, characterized by Th17 cells.…”