TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis

Abstract

BackgroundExperimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4+ T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.FindingsHost mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE.ConclusionsDC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.

Lipopolysaccharide directly stimulates Th17 differentiation in vitro modulating phosphorylation of RelB and NF-κB1

“…Although we provide evidence that LPS directly stimulates the differentiation of Th17 cells in vitro, it remains to be studied whether LPS works directly on Th17 differentiation or indirectly via APC in vivo, as previously reported [3][4][5].…”

“…LPS either inhibits or stimulates the induction of EAE by regulating antigen presenting abilities of dendritic cells [4,[56][57][58].…”

“…Interestingly, expression of TLR1, TLR2, TLR6, and TLR4 is much higher in Th17 cells than in Th1 and Th2 cells [11]. Thus, it is possible that LPS regulates Th17 differentiation directly rather than indirectly via activation of macrophages and dendritic cells by TLR4 ligand [3][4][5].…”

“…So far about 13 TLRs in mice, 10 peptidoglycan, CpG DNA, and double-stranded or single-stranded RNA derived from bacterial or viral microorganisms [2]. It was initially thought that TLRs are preferentially expressed in innate immune cells, such as macrophages and dendritic cells, and activation of these cells by the interaction of a TLR and its ligand indirectly leads to the activation of cells of the adaptive immune system, especially T cells [3][4][5]. However, it is evident that some of TLRs are expressed in various subsets of ␣␤T cells as well as ␥␦T cells [6,7].…”

Myocardial expression of Toll‐like receptor 4 predicts the response to immunosuppressive therapy in patients with virus‐negative chronic inflammatory cardiomyopathy

“…Several experimental and human studies have suggested a potential role of Toll‐like receptors (TLRs), molecular components that regulate the innate immune system, in the induction and perpetuation of inflammation in autoimmune diseases . Specifically, the cell surface Toll‐like receptor 4 (TLR4) has been implicated in the development of several experimental and human autoimmune disorders, including experimental autoimmune encephalomyelitis, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, type 1 diabetes, and multiple sclerosis …”