Opposing Roles of Dectin-1 Expressed on Human Plasmacytoid Dendritic Cells and Myeloid Dendritic Cells in Th2 Polarization

Joo, Hye Mee; Upchurch, Katherine; Zhang, Wei; Ni, Ling; Li, Dapeng; Xue, Yaming; Li, Xiao Hua; Hori, Tomohide; Zurawski, Sandra; Liu, Yong Jun; Oh, Sang Kon

doi:10.4049/jimmunol.1402276

Cited by 32 publications

(41 citation statements)

References 45 publications

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“…While ligation of ITIM-associated LLR, such as myeloid C-type lectin-like receptor (MICL) or DCIR in cDCs inhibits TLR4 and TLR8 signaling (24, 33, 34), suppression of TLR signaling by ligation of ITAM-associated LLRs in cDCs has not been reported (28). These results together with the recent observation showing that Dectin-1-activated pDCs promote Th2-type T cell responses while Dectin-1-activated cDCs do the opposite, point to the importance of combination of PAMP, PRR, and the cell context in the regulation of adaptive immune responses by innate immunity (4, 35). …”

Section: Immunogenic and Tolerogenic Receptors Of Dcssupporting

confidence: 58%

Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells

et al. 2017

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The innate immune cells sense microbial infection and self-ligands by pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) and regulatory receptors (RRs), associated with immunoreceptor tyrosine-based activation motif (ITAM). Rapid activation and concerted action of PRRs signaling and feedback inhibitory mechanisms must be engaged to ensure the host defense functions and to prevent cytotoxicity associated with excessive activation. ITAM-associated RRs can generate stimulatory or, paradoxically, inhibitory signals. The network of ITAM-associated RR, together with TLR-signaling pathways, are responsible for immunogenic or tolerogenic responses of macrophages and dendritic cells to their microenvironment. In macrophages, TLR4 signaling is inhibited by low-avidity ligation of ITAM-associated receptors, while high-avidity ligation of ITAM-associated receptors results in potentiation of TLR4 signaling together with resistance to extracellular cytokine microenvironment signals. In contrast to macrophages, TLR7/9 signaling in plasmacytoid DCs (pDCs) is inhibited by high-avidity ligation of ITAM-associated RR, while low-avidity ligation does not show any effect. Surprisingly, interference of ITAM-associated receptor signaling with TLR pathways has not been reported in conventional dendritic cells. Here, we present an overview of molecular mechanisms acting at the crossroads of TLR and ITAM-signaling pathways and address the question of how the high-avidity engagement of the ITAM-associated receptors in pDCs inhibits TLR7/9 signaling. Cellular context and spatiotemporal engagement of ITAM- and TLR-signaling pathways are responsible for different outcomes of macrophage versus pDC activation. While the cross-regulation of cytokine and TLR signaling, together with antigen presentation, are the principal functions of ITAM-associated RR in macrophages, the major role of these receptors in pDCs seems to be related to inhibition of cytokine production and reestablishment of a tolerogenic state following pDC activation. Pharmacologic targeting of TLR and ITAM signaling could be an attractive new therapeutic approach for treatment of chronic infections, cancer, and autoimmune and inflammatory diseases related to pDCs.

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Section: Immunogenic and Tolerogenic Receptors Of Dcssupporting

confidence: 58%

Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells

et al. 2017

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“…For example, DECTIN-1 signaling in DCs has been shown to influence T-cell polarization fate by modulating also the expression of the costimulatory molecules OX40 ligand. 37 We found that CLEC-1 ligation does not induce by itself nor does it modulate the zymosan-induced activation of the SYK-dependent canonical NF-kB pathway. Nevertheless, we observed changes in the phosphorylation pattern of CLEC-1-binding partners.…”

Section: Cd25mentioning

confidence: 86%

Cell-surface C-type lectin-like receptor CLEC-1 dampens dendritic cell activation and downstream Th17 responses

et al. 2017

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Key Points• CLEC-1 is restricted to CD16 2 myeloid DCs in human blood and acts as an inhibitory receptor to restrain downstream Th17 activation.• CLEC-1-deficient rats highlight an in vivo function for CLEC-1 in preventing excessive T-cell priming and effector Th responses.Dendritic cells (DCs) represent essential antigen-presenting cells that are critical for linking innate and adaptive immunity, and influencing T-cell responses. Among pattern recognition receptors, DCs express C-type lectin receptors triggered by both exogenous and endogenous ligands, therefore dictating pathogen response, and also shaping T-cell immunity.We previously described in rat, the expression of the orphan C-type lectin-like receptor-1 (CLEC- 1) by DCs and demonstrated in vitro its inhibitory role in downstream T helper 17 (Th17)activation. In this study, we examined the expression and functionality of CLEC-1 in human DCs, and show a cell-surface expression on the CD16 2 subpopulation of blood DCs and on monocytederived DCs (moDCs). CLEC-1 expression on moDCs is downregulated by inflammatory stimuli and enhanced by transforming growth factor b. Moreover, we demonstrate that CLEC-1 is a functional receptor on human moDCs and that although not modulating the spleen tyrosine kinase-dependent canonical nuclear factor-kB pathway, represses subsequent Th17 responses.Interestingly, a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and is associated with a higher level of interleukin 17A (IL17A). Importantly, using CLEC-1-deficient rats, we showed that disruption of CLEC-1 signaling led to an enhanced Il12p40 subunit expression in DCs, and to an exacerbation of downstream in vitro and in vivo CD4 1 Th1 and Th17 responses. Collectively, our results establish a role for CLEC-1 as an inhibitory receptor in DCs able to dampen activation and downstream effector Th responses. As a cell-surface receptor, CLEC-1 may represent a useful therapeutic target for modulating T-cell immune responses in a clinical setting.

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“…2). Transcription of IL12A, encoding the IL-12p35 subunit, depends on chromatin remodelling to allow the 52 . RAF1 activation by dectin 1 also induces epigenetic reprogramming in monocytes, thereby enhancing innate antifungal immunity by monocytes upon a second exposure to the pathogen 53 , and it is conceivable that this process is important in reinforcing adaptive immunity.…”

Section: Dectin 1 Induces T H 1 and T H 17 Cell Responsesmentioning

confidence: 99%

C-type lectin receptors in the control of T helper cell differentiation

2016

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Pathogen recognition by C-type lectin receptors (CLRs) expressed by dendritic cells is important not only for antigen presentation, but also for the induction of appropriate adaptive immune responses via T helper (TH) cell differentiation. CLRs act either by themselves or in cooperation with other receptors, such as other CLRs, Toll-like receptors and interferon receptors, to induce signalling pathways that trigger specialized cytokine programmes for polarization of TH cell differentiation. In this Review, we discuss how triggering of the prototypical CLRs leads to distinct pathogen-tailored TH cell responses and how we can harness our expanding knowledge for vaccine design and the treatment of inflammatory and malignant diseases.

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Opposing Roles of Dectin-1 Expressed on Human Plasmacytoid Dendritic Cells and Myeloid Dendritic Cells in Th2 Polarization

Cited by 32 publications

References 45 publications

Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells

Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells

Cell-surface C-type lectin-like receptor CLEC-1 dampens dendritic cell activation and downstream Th17 responses

C-type lectin receptors in the control of T helper cell differentiation

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