Soluble CD83 ameliorates experimental colitis in mice

Eckhardt, Jenny; Kreiser, Simon; Döbbeler, M.; Nicolette, Charles A.; DeBenedette, Mark; Tcherepanova, Irina Y.; Ostalecki, Christian; Pommer, Ansgar J.; Becker, Christoph; Günther, Claudia; Zinser, Elisabeth; Mak, Tak W.; Steinkasserer, Alexander; Lechmann, Matthias

doi:10.1038/mi.2013.119

Cited by 41 publications

(42 citation statements)

References 47 publications

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“…In our model, a lack of IRAK-1 protein results in a shift to an anti-inflammatory state characterized by PGE 2 and IL-10 secretion. Additionally, sCD83 was shown to prevent experimental autoimmune encephalomyelitis (25) and colitis (26) in murine models, both of which were shown to be critically dependent on IRAK-1 activity (51,72). Interestingly, we saw no evidence for upregulation of IRAK-M, the pseudokinase shown to be a negative regulator of TLR signaling (73).…”

Section: Discussionmentioning

confidence: 66%

“…In vitro evaluations showed that recombinant CD83 protein preparations inhibits T cell proliferation in vitro (22)(23)(24). Moreover, recombinant sCD83 protein reduced the symptoms associated with models of experimental autoimmune encephalomyelitis (25) and murine experimental colitis (26) and, when applied topically, prevented corneal graft rejection (27). The underlying mechanism by which sCD83 mediates its regulatory properties is not clear.…”

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confidence: 99%

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Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Horvatinovich

Grogan

Norris

et al. 2017

The Journal of Immunology

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The transmembrane protein CD83, expressed on APCs, B cells, and T cells, can be expressed as a soluble form generated by alternative splice variants and/or by shedding. Soluble CD83 (sCD83) was shown to be involved in negatively regulating the immune response. sCD83 inhibits T cell proliferation in vitro, supports allograft survival in vivo, prevents corneal transplant rejection, and attenuates the progression and severity of autoimmune diseases and experimental colitis. Although sCD83 binds to human PBMCs, the specific molecules that bind sCD83 have not been identified. In this article, we identify myeloid differentiation factor-2 (MD-2), the coreceptor within the TLR4/MD-2 receptor complex, as the high-affinity sCD83 binding partner. TLR4/MD-2 mediates proinflammatory signal delivery following recognition of bacterial LPSs. However, altering TLR4 signaling can attenuate the proinflammatory cascade, leading to LPS tolerance. Our data show that binding of sCD83 to MD-2 alters this signaling cascade by rapidly degrading IL-1R–associated kinase-1, leading to induction of the anti-inflammatory mediators IDO, IL-10, and PGE2 in a COX-2–dependent manner. sCD83 inhibited T cell proliferation, blocked IL-2 secretion, and rendered T cells unresponsive to further downstream differentiation signals mediated by IL-2. Therefore, we propose the tolerogenic mechanism of action of sCD83 to be dependent on initial interaction with APCs, altering early cytokine signal pathways and leading to T cell unresponsiveness.

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Section: Discussionmentioning

confidence: 66%

mentioning

confidence: 99%

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Horvatinovich

Grogan

Norris

et al. 2017

The Journal of Immunology

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“…Sample preparations from tissue, data generation, and analysis were performed as described previously (22). ImageJ software was used to determine the size of DZ and LZ within the GC.…”

Section: Immunofluorescencementioning

confidence: 99%

“…This form of sCD83 possesses immunomodulatory effects, as recombinant sCD83 inhibits DC maturation and subsequently DC-mediated T cell stimulation (20). Application of sCD83 into mice reduces severity of autoimmune diseases and induces prolonged graft survival (21)(22)(23).…”

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confidence: 99%

CD83 Modulates B Cell Activation and Germinal Center Responses

Krzyzak

Seitz

Urbat

et al. 2016

The Journal of Immunology

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CD83 is a maturation marker for dendritic cells. In the B cell lineage, CD83 is expressed especially on activated B cells and on light zone B cells during the germinal center (GC) reaction. The function of CD83 during GC responses is unclear. CD83−/− mice have a strong reduction of CD4+ T cells, which makes it difficult to analyze a functional role of CD83 on B cells during GC responses. Therefore, in the present study we generated a B cell–specific CD83 conditional knockout (CD83 B-cKO) model. CD83 B-cKO B cells show defective upregulation of MHC class II and CD86 expression and impaired proliferation after different stimuli. Analyses of GC responses after immunization with various Ags revealed a characteristic shift in dark zone and light zone B cell numbers, with an increase of B cells in the dark zone of CD83 B-cKO mice. This effect was not accompanied by alterations in the level of IgG immune responses or by major differences in affinity maturation. However, an enhanced IgE response was observed in CD83 B-cKO mice. Additionally, we observed a strong competitive disadvantage of CD83-cKO B cells in GC responses in mixed bone marrow chimeras. Furthermore, infection of mice with Borrelia burgdorferi revealed a defect in bacterial clearance of CD83 B-cKO mice with a shift toward a Th2 response, indicated by a strong increase in IgE titers. Taken together, our results show that CD83 is important for B cell activation and modulates GC composition and IgE Ab responses in vivo.

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“…Using animal models, it could be demonstrated that a recombinant expressed sCD83 molecule inhibits disease-associated symptoms in experimental autoimmune encephalomyelitis as well as in an inflammatory bowel disease model. In addition, sCD83 was shown to prevent graft rejection in different transplantation models (13)(14)(15)(16)(17).…”

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confidence: 99%

L Particles Transmit Viral Proteins from Herpes Simplex Virus 1-Infected Mature Dendritic Cells to Uninfected Bystander Cells, Inducing CD83 Downmodulation

Heilingloh

Kummer

Mühl-Zürbes

et al. 2015

J Virol

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Mature dendritic cells (mDCs) are known as the most potent antigen-presenting cells (APCs) since they are also able to prime/ induce naive T cells. Thus, mDCs play a pivotal role during the induction of antiviral immune responses. Remarkably, the cell surface molecule CD83, which was shown to have costimulatory properties, is targeted by herpes simplex virus 1 (HSV-1) for viral immune escape. Infection of mDCs with HSV-1 results in downmodulation of CD83, resulting in reduced T cell stimulation. In this study, we report that not only infected mDCs but also uninfected bystander cells in an infected culture show a significant CD83 reduction. We demonstrate that this effect is independent of phagocytosis and transmissible from infected to uninfected mDCs. The presence of specific viral proteins found in these uninfected bystander cells led to the hypothesis that viral proteins are transferred from infected to uninfected cells via L particles. These L particles are generated during lytic replication in parallel with full virions, called H particles. L particles contain viral proteins but lack the viral capsid and DNA. Therefore, these particles are not infectious but are able to transfer several viral proteins. Incubation of mDCs with L particles indeed reduced CD83 expression on uninfected bystander DCs, providing for the first time evidence that functional viral proteins are transmitted via L particles from infected mDCs to uninfected bystander cells, thereby inducing CD83 downmodulation. Dendritic cells (DCs) are known as the most potent antigenpresenting cells (APCs) due to their unique ability to prime naive T cells. Thus, they are vital to induce effective antiviral immune responses. In their immature state, DCs reside as sentinels of the immune system in almost all peripheral tissues until they encounter and take up antigens, resulting in maturation of DCs. As a consequence, expression of major histocompatibility complex (MHC) classes I and II as well as of costimulatory molecules, such as CD40, CD80, CD86, and also CD83, is strongly induced (1-3). As CD83 is not expressed on immature, tolerogenic DCs but is highly upregulated during DC maturation, this protein has become one of the best surface markers for mature DCs (3-5). Nevertheless, CD83 is also expressed on subsets of activated T cells, B cells, granulocyte precursor cells, myelocytes, neutrophils, and thymus epithelial cells as well as on regulatory T cells (5-10).In addition to this membrane-bound CD83 molecule (mCD83), a soluble form of CD83 (sCD83), consisting of the extracellular Ig domain of mCD83, also has been described previously (11,12). This soluble form, which was shown to possess potent immunosuppressive properties, is released from activated DCs as well as from B cells and can be detected at low levels in sera of healthy individuals (11) and at highly elevated concentrations in patients suffering from malignant disorders (12). Using animal models, it could be demonstrated that a recombinant expressed sCD83 molecule inhibits disea...

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Soluble CD83 ameliorates experimental colitis in mice

Cited by 41 publications

References 47 publications

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

Soluble CD83 Inhibits T Cell Activation by Binding to the TLR4/MD-2 Complex on CD14+ Monocytes

CD83 Modulates B Cell Activation and Germinal Center Responses

L Particles Transmit Viral Proteins from Herpes Simplex Virus 1-Infected Mature Dendritic Cells to Uninfected Bystander Cells, Inducing CD83 Downmodulation

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