Flagellin Modulates the Function of Invariant NKT Cells From Patients With Asthma via Dendritic Cells

Abstract

PurposeInvariant natural killer T (iNKT) cells play a critical role in the pathogenesis of asthma. We previously reported the association between circulating Th2-like iNKT cells and lung function in asthma patients and the suppressive effect of Toll-like receptor 5 ligand flagellin B (FlaB) on asthmatic in a mouse model. Thus, we investigated whether FlaB modulates the function of circulating iNKT cells in asthmatic patients.MethodsPeripheral blood mononuclear cells (PBMCs) were treated with FlaB, and the secreted and intracellular cytokines of iNKT cells were evaluated by using ELISA and flow cytometry, respectively, following stimulation with α-galactosylceramide. Foxp3+ iNKT cells were also measured. To determine the effect of FlaB-treated dendritic cells (DCs) on iNKT cells, we co-cultured CD14+ monocyte-derived DCs and T cells from patients with house dust mite-sensitive asthma and analyzed intracellular cytokines in iNKT cells.ResultsA reduction of IL-4 and IL-17 production by iNKT cells in PBMCs after FlaB treatment was alleviated following blocking of IL-10 signaling. A decrease in the frequencies of IL-4+ and IL-17+ iNKT cells by FlaB-treated DCs was reversed after blocking of IL-10 signaling. Simultaneously, an increase in Foxp3+ iNKT cells induced by FlaB treatment disappeared after blocking of IL-10.ConclusionsFlaB may inhibit Th2- and Th17-like iNKT cells and induce Foxp3+ iNKT cells by DCs via an IL-10-dependent mechanism in asthmatic patients. In patients with a specific asthma phenotype associated with iNKT cells, FlaB may be an effective immunomodulator for iNKT cell-targeted immunotherapy.

Toll‐like receptor 5 signaling restrains T‐cell/natural killer T‐cell activation and protects against concanavalin A–induced hepatic injury

“…This conclusion was consistent with previous studies, which demonstrated that long‐term flagellin exposure was capable of inducing NKT‐cell anergy . Moreover, the TLR5 agonist flagellin B displayed optimal suppressive activities on NKT cell‐mediated Th1‐like, Th2‐like, and Th17‐like responses by inducing regulatory dendritic cells and T cells in experimental asthma mice or patients with asthma . Tregs expressed high levels of TLR5 mRNA, and treatment of Tregs with flagellin was reported to enhance the regulatory activity of these cells .…”

“…(21) Moreover, the TLR5 agonist flagellin B displayed optimal suppressive activities on NKT cell-mediated Th1-like, Th2-like, and Th17like responses by inducing regulatory dendritic cells and T cells in experimental asthma mice or patients with asthma. (22) Tregs expressed high levels of TLR5 mRNA, and treatment of Tregs with flagellin was reported to enhance the regulatory activity of these cells. (23) We found that CBLB502 pretreatment increased CD4 1 CD25 1 FoxP3 1 Tregs in the liver, which has been shown to suppress immune responses and to be involved in protection of Con A-induced hepatitis.…”

“…NKT cells preactivated by flagellin displayed hyporesponsiveness toward α‐galactosylceramide (α‐Galcer) or Con A restimulation 3 weeks later, thereby demonstrating the unique role of TLR5 signaling in modulating the activity of NKT cells, a critical cell type that has been extensively implicated in the pathogenesis of inflammatory human diseases. The TLR5 agonist flagellin B has been shown to inhibit the function of T helper 2 (Th2)–like and Th17‐like NKT cells in patients with asthma . Moreover, flagellin has immunosuppressive roles by activating recipient regulatory T cells (Tregs), suggesting a potent immune tolerance application of the TLR5 agonist.…”

“…The TLR5 agonist flagellin B has been shown to inhibit the function of T helper 2 (Th2)-like and Th17-like NKT cells in patients with asthma. (22) Moreover, flagellin has immunosuppressive roles by activating recipient regulatory T cells (Tregs), (23) suggesting a potent immune tolerance application of the TLR5 agonist. For example, administration of flagellin could attenuate graft-versus-host disease and reduce proinflammatory cytokines produced by activated donor T cells in an allogeneic bone marrow (BM) transplantation model.…”

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“…Overall, activation of TLR5 by flagellin or Entolimod triggers a robust immunological response that engages a broad range of immune cell types that participate in both innate and adaptive immune systems (Honko and Mizel 2005;Mizel and Bates 2010;Hossain et al 2014;Brackett et al 2016;Shim et al 2016).…”