TLR2 &amp; Co: a critical analysis of the complex interactions between TLR2 and coreceptors

Bergenhenegouwen, Jeroen van; Plantinga, Theo S.; Joosten, Leo A. B.; Netea, Mihai G.; Folkerts, Gert; Kraneveld, Aletta D.; Garssen, Johan; Vos, Anneke S. de

doi:10.1189/jlb.0113003

Cited by 127 publications

(107 citation statements)

References 246 publications

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“…Triggering of TLRs has been implicated in both beneficial and detrimental effects in antitumor immunity, with the detrimental effects mostly being inflicted by direct interactions of TLR-Ls with TLRs expressed on tumor cells (29)(30)(31). We and others have observed strong immune-potentiating effects of TLR2 triggering (16,32) as well as its effects in tumor eradication (14,33). Indeed, the in vivo experiments in the present study show strong induction of antitumor immunity when a TLR2-L is covalently conjugated to the antigen (Figs.…”

Section: Discussionmentioning

confidence: 97%

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Zom

Khan

Britten

et al. 2014

Cancer Immunology Research

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Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic synthetic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8þ T-cell immune responses. Previously, we have shown that the mechanism underlying the power of TLR-L SLP conjugates is improved delivery of the antigen together with a dendritic cell activation signal. In the present study, we have expanded the approach to tumor-specific CD4 þ as well as CD8 þ T-cell responses and in vivo studies in two nonrelated aggressive tumor models. We show that TLR2-L SLP conjugates have superior mouse CD8 þ and CD4

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Section: Discussionmentioning

confidence: 97%

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Zom

Khan

Britten

et al. 2014

Cancer Immunology Research

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“…For instance, the concentration of gp96 in synovial fluid is greater in patients with rheumatoid arthritis compared with patients with other forms of inflammatory arthritis, and gp96 promotes synovial inflammation through TLR2 signaling (32). As a consequence, in patients with rheumatoid arthritis, blockade of TLR2 prevents the release of inflammatory mediators by synovial tissue (33). Among these mediators, IL-17 is predominantly involved in the induction and progression of rheumatoid arthritis (34).…”

Section: Extracellular Calpains Regulate Il-17 Expression In Vivomentioning

confidence: 99%

Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

Perez

Dansou

Hervé

et al. 2016

The Journal of Immunology

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Calpains are intracellular proteases that play a key role in inflammation/immunity. Rare studies show that they are partially externalized. However, the mechanism of this secretion and the functions of exteriorized calpains remain poorly understood. In this study, we found that mouse and human lymphocytes secreted calpains through an ABCA1-driven process. In turn, extracellular calpains inhibited IL-17A expression. We were able to attribute this function to a cleavage of the TLR2 extracellular domain, which prevented TLR2-induced transcription of molecules essential for IL-17A induction. Calpain exteriorization and TLR2 cleavage were critical for the control of IL-17A expression by low doses of IL-2. By using newly developed transgenic mice in which extracellular calpains are specifically inactivated, we provide evidence for the relevance of calpain externalization in vivo in regulating IL-17A expression and function in experimental sterile peritonitis and autoimmune arthritis, respectively. Thus, this study identifies calpain exteriorization as a potential target for immune modulation.

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“…Previously, the integrin regulation of TLRs has been documented in nonepithelial cells (38). Thus, ␣M␤2 integrin (CD11b/ CD18) regulates TLR signaling in monocytes/macrophages and in dendritic cells.…”

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confidence: 99%

αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors

Casiraghi

Gianni

Campadelli-Fiume

2016

J Virol

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We report that ␣v␤3 integrin strongly affects the innate immune response in epithelial cells. ␣v␤3 integrin greatly increased the response elicited via plasma membrane Toll-like receptors (TLRs) by herpes simplex virus or bacterial ligands. The endosomal TLR3, not the cytosolic sensor interferon gamma-inducible protein 16 (IFI16), was also boosted by ␣v␤3 integrin. The boosting was exerted specifically by ␣v␤3 integrin but not by ␣v␤6 or ␣v␤8 integrin. Current and previous work indicates that integrin-TLR cooperation occurs in epithelial and monocytic cells. The TLR response should be considered an integrin-TLR response. The Toll-like receptors (TLRs) constitute the first line of defense against invading pathogens (1). They include TLR1, TLR2, and TLR4 to TLR6, which are localized at the plasma membrane, and TLR3, TLR7, and TLR9, which are localized at endosomal membranes (1). TLR2 can be expressed as a homodimer or as a heterodimer with TLR1 or TLR6. The plasma membrane TLRs recognize pathogen-associated molecular patterns (PAMPs) present on the surfaces of bacteria (e.g., lipopolysaccharide [LPS], flagellin) or of viruses (e.g., virion envelope glycoproteins). The endosomal TLRs recognize viral or bacterial DNA or RNA.Integrins are cell surface glycoproteins involved in cell-cell and cell-matrix interactions. They are composed of an ␣ and a ␤ subunit (2-4). They serve as receptors for several viruses, including some herpesviruses (5-10). Our laboratory investigated the role played by integrins in herpes simplex virus (HSV) entry and found that ␣v␤6 and ␣v␤8 integrins serve as interchangeable receptors for HSV entry into epithelial and neuronal cells (11). They bind the envelope glycoproteins gH and gL (gH/gL), a heterodimeric component of the fusion machinery, with high affinity (11). Their interaction with gH/gL promotes virion endocytosis and the displacement of gL from gH, most likely as part of the process of gH activation (12). An additional integrin involved in HSV entry is ␣v␤3, which serves two functions. It binds gH/gL at low affinity and routes HSV to lipid rafts and an acidic endosomal pathway of entry and thus serves as a routing factor (13). Importantly, it contributes to the innate immune response through a concerted action with TLR2 (14-16). In epithelial cell lines, including keratinocytic and neuronal cells, interferon alpha (IFN-␣) and IFN-␤, interleukin 2, and interleukin 10 are upregulated, and NF-B is activated in response to HSV or to LPS (14). This response is strongly impaired in the absence of TLR2 or upon ␤3-integrin depletion. The HSV PAMP is gH/gL, which simultaneously binds ␣v␤3 integrin and TLR2 and thus cross-links the two receptors (14). The basis of the concerted ␣v␤3 integrin-TLR2 response rests in boosting by ␣v␤3 integrin of MYD88-dependent TLR2 signaling (16).Here, we asked whether the concerted integrin-TLR response is a broader phenomenon that involves epithelial integrins other than ␣v␤3 (e.g., ␣v␤6 and ␣v␤8) or additional TLRs. To address this question, 293T cells and t...

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TLR2 & Co: a critical analysis of the complex interactions between TLR2 and coreceptors

Cited by 127 publications

References 246 publications

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates

Calpains Released by T Lymphocytes Cleave TLR2 To Control IL-17 Expression

αvβ3 Integrin Boosts the Innate Immune Response Elicited in Epithelial Cells through Plasma Membrane and Endosomal Toll-Like Receptors

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