Toll-like Receptor 2 Signaling in CD4+ T Lymphocytes Promotes T Helper 17 Responses and Regulates the Pathogenesis of Autoimmune Disease

Reynolds, Joseph M.; Pappu, Bhanu P.; Peng, Juan; Martínez, Gustavo; Zhang, Yongliang; Chung, Yeonseok; Ma, Li; Yang, Xuexian O.; Nurieva, Roza; Tian, Qiang; Dong, Chen

doi:10.1016/j.immuni.2010.04.010

Cited by 263 publications

(314 citation statements)

References 33 publications

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“…Ligation of TLR-2 can exacerbate experimental autoimmune encephalomyelitis (28). Recently, this has been attributed to enhanced Th17 production (29). We found that TLR-2 ligation resulted in persistent elevation of Th17 autoimmune responses, which facilitated the development of neutrophil-mediated glomerulonephritis after administration of sheep anti- Figure 6.…”

Section: Discussionmentioning

confidence: 69%

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Summers¹,

Steinmetz²,

Gan³

et al. 2011

Arthritis & Rheumatism

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Objective. Autoantibodies constitute the hallmark of antineutrophil cytoplasmic antibody-associated vasculitis (AAV); however, CD4؉ T cells play an essential role in the development of autoimmunity. Infection is associated with vasculitis, with Toll-like receptors (TLRs) a potential link between infection and autoimmunity. This study was undertaken to investigate the role of TLR ligation on cellular and humoral autoimmunity and glomerular injury in experimental myeloperoxidase (MPO)-induced AAV.Methods. We analyzed autoimmune responses in wild-type mice immunized with MPO alone or coimmunized with MPO and a TLR-2 or TLR-9 ligand. The major vascular injury found in human disease, glomerulonephritis with focal necrosis, was triggered by administering a subnephritogenic dose of nephrotoxic serum.Results. MPO alone induced low-titer antineutrophil cytoplasmic antibodies (ANCAs) without delayedtype hypersensitivity or CD4 cytokine responses. However, when MPO was given with either TLR ligand, cellular and humoral autoimmunity was enhanced, but with distinctly different CD4 subsets and IgG ANCA isotypes. TLR-2 ligand induced Th17 autoimmunity, with retinoic acid receptor-related orphan nuclear receptor ␥t-dependent interleukin-17A (IL-17A) production. TLR-9 ligand promoted Th1 autoimmunity, with enhanced production of interferon-␥ (IFN␥) and Th1-associated IgG subclasses. Glomerular vasculitis developed only after the administration of nephrotoxic serum in mice immunized with either TLR ligand and MPO. Glomerulonephritis directed by MPO and TLR-2 ligation was attenuated when IL-17A was neutralized, while glomerulonephritis induced by MPO and TLR-9 ligation was attenuated when IFN␥ was neutralized.Conclusion. Our findings indicate a pathogenic role of TLRs in initiating autoimmune AAV. TLR-2 induces Th17 CD4 cells while TLR-9 can also direct vasculitis, by directing Th1 autoimmunity.

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Section: Discussionmentioning

confidence: 69%

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Summers¹,

Steinmetz²,

Gan³

et al. 2011

Arthritis & Rheumatism

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“…EAE is attenuated in TLR2 -/-mice, suggesting that the TLR2 signaling pathway may be a drug target for the treatment or prevention of multiple sclerosis 62 . An antibody to TLR2 developed by Opsona Therapeutics has been shown to be effective in a murine model of myocardial ischemia reperfusion injury 103 , and a humanized version of the antibody (OPN-305) has recently entered phase I clinical trials.…”

Section: Tlrs and Other Pprs As Drug Targets For Autoimmunitymentioning

confidence: 99%

TLR-dependent T cell activation in autoimmunity

2011

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Autoimmune disease can develop as a result of a breakdown in immunological tolerance, leading to the activation of self-reactive T cells. There is an established link between infection and human autoimmune diseases. Furthermore, experimental autoimmune diseases can be induced by immunization with autoantigens that are administered together with complete Freund's adjuvant containing killed Mycobacteria tuberculosis, which in some cases can be replaced with individual pathogen-associated molecular patterns (PAMPs). Exogenous PAMPs and endogenous danger signals from necrotic cells bind to pathogen recognition receptors, including Toll-like receptors, and activate signaling pathways in innate immune cells and on T cells, leading to inflammatory cytokine production and T cell activation, and this is now considered to be a major factor in the development of autoimmunity.

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“…It is known that TLR stimulation of innate immune cells promotes Th1 and Th17 responses by inducing the Th1-polarizing cytokine IL-12 and the Th17-polarizing cytokines IL-6/IL-23/ IL-1 (refs 1,41). Recent studies, including ours, show that TLR2 ligands directly activate Th1 but not Th2 cells 7 and promote Th17 differentiation 8 . In contrast to TLR, the activation of RLRs suppresses Th1 and Th17 differentiation through the inhibition of IL-12 and IL-23 production, resulting in the enhanced differentiation of Th2 cells 31 .…”

Section: Discussionmentioning

confidence: 64%

“…For example, TLR2 ligands directly promote proliferation of activated T cells 3,4 , modulate the proliferation and suppressive functions of CD4 þ CD25 þ regulatory T cells 5,6 , trigger Th1 effector functions independently of TCR stimulation 7 and modulate Th17 responses 8 .…”

mentioning

confidence: 99%

Nucleic acid sensing by T cells initiates Th2 cell differentiation

et al. 2014

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While T-cell responses are directly modulated by Toll-like receptor (TLR) ligands, the mechanism and physiological function of nucleic acids (NAs)-mediated T cell costimulation remains unclear. Here we show that unlike in innate cells, T-cell costimulation is induced even by non-CpG DNA and by self-DNA, which is released from dead cells and complexes with antimicrobial peptides or histones. Such NA complexes are internalized by T cells and induce costimulatory responses independently of known NA sensors, including TLRs, RIG-I-like receptors (RLRs), inflammasomes and STING-dependent cytosolic DNA sensors. Such NA-mediated costimulation crucially induces Th2 differentiation by suppressing T-bet expression, followed by the induction of GATA-3 and Th2 cytokines. These findings unveil the function of NA sensing by T cells to trigger and amplify allergic inflammation.

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Toll-like Receptor 2 Signaling in CD4+ T Lymphocytes Promotes T Helper 17 Responses and Regulates the Pathogenesis of Autoimmune Disease

Cited by 263 publications

References 33 publications

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

TLR-dependent T cell activation in autoimmunity

Nucleic acid sensing by T cells initiates Th2 cell differentiation

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