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

Lookup NU author(s): Dr Henrique De Paula LemosORCiD, Emeritus Professor Andrew MellorORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


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.

Publication metadata

Author(s): Horvatinovich JM, Grogan EW, Norris M, Steinkasserer A, Lemos H, Mellor AL, Tcherepanova IY, Nicolette CA, DeBenedette MA

Publication type: Article

Publication status: Published

Journal: The Journal of Immunology

Year: 2017

Volume: 198

Issue: 6

Pages: 2286-2301

Print publication date: 15/03/2017

Online publication date: 13/02/2017

Acceptance date: 13/01/2017

Date deposited: 21/11/2017

ISSN (print): 0022-1767

ISSN (electronic): 1550-6606

Publisher: American Association of Immunologists


DOI: 10.4049/jimmunol.1600802

PubMed id: 28193829


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