Tilting the Balance: Therapeutic Prospects of CD83 as a Checkpoint Molecule Controlling Resolution of Inflammation

Abstract

Chronic inflammatory diseases and transplant rejection represent major challenges for modern health care. Thus, identification of immune checkpoints that contribute to resolution of inflammation is key to developing novel therapeutic agents for those conditions. In recent years, the CD83 (cluster of differentiation 83) protein has emerged as an interesting potential candidate for such a “pro-resolution” therapy. This molecule occurs in a membrane-bound and a soluble isoform (mCD83 and sCD83, respectively), both of which are involved in resolution of inflammation. Originally described as a maturation marker on dendritic cells (DCs), mCD83 is also expressed by activated B and T cells as well as regulatory T cells (Tregs) and controls turnover of MHC II molecules in the thymus, and thereby positive selection of CD4+ T cells. Additionally, it serves to confine overshooting (auto-)immune responses. Consequently, animals with a conditional deletion of CD83 in DCs or regulatory T cells suffer from impaired resolution of inflammation. Pro-resolving effects of sCD83 became evident in pre-clinical autoimmune and transplantation models, where application of sCD83 reduced disease symptoms and enhanced allograft survival, respectively. Here, we summarize recent advances regarding CD83-mediated resolution of inflammatory responses, its binding partners as well as induced signaling pathways, and emphasize its therapeutic potential for future clinical trials.

Soluble CD83 improves and accelerates wound healing by the induction of pro-resolving macrophages

“…Amongst others, administration of sCD83 ameliorated disease progression in murine autoimmune models such as experimental autoimmune encephalomyelitis (EAE), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD) and antigen-induced arthritis (AIA) (6,15,24,25,50). Analogously, administration of sCD83 significantly improved graft survival in transplantation models of cornea, heart, kidney, and skin, which depended on the IDO1-mediated induction of Treg differentiation and proliferation (9,11,(51)(52)(53). In the present study, we report for the first time the pro-regenerative effects of sCD83 on cutaneous wound healing.…”

“…The membranebound form of CD83 (mCD83) expressed by TECs is absolutely essential for the positive selection and development of CD4 + T cells in the thymus (7). In addition, our group recently reported that mCD83 expression by Tregs is crucial for their development and that the specific deletion of CD83 on Tregs leads to exacerbated autoimmune pathologies and impaired resolution of inflammation (8,9). Furthermore, specific conditional KO CD83 in DC leads to excessive inflammatory immune responses and drastically increased autoimmunity (10).…”

CD83 expressed by macrophages is an important immune checkpoint molecule for the resolution of inflammation

“…Microarray analyses revealed that the Cd83 transcript is specifically induced in AAM but not CAM ( 7 ). The corresponding membrane bound CD83 (mCD83) glycoprotein, which is expressed on activated immune cells, has been described to have potent immunomodulatory properties ( 12 , 13 ). Furthermore, CD83 inhibits the ubiquitin-dependent degradation of MHC-II and CD86 on DCs as well as MHC-II on thymic epithelial cells, mediated by MARCH1 and MARCH8 respectively, thereby stabilizing the surface expression of these important molecules ( 14 , 15 ).…”

“…Moreover, CD83 expressed by DCs and regulatory T cells (Tregs) plays a central role in promoting resolution of inflammation ( 16 , 17 ). In addition, a soluble isoform of CD83 (sCD83) has also been described, having profound immunomodulatory properties in murine autoimmune and transplantation models ( 12 , 13 , 18 , 19 ). Recently, we reported that sCD83 induces pro-resolving Mφ, thereby improving corneal transplant survival ( 20 ) as well as skin wound healing processes ( 21 ).…”

The relation of the frequency and functional molecules expression on plasmacytoid dendritic cells to postpartum hepatitis in women with HBeAg-positive chronic hepatitis B virus infection

“…At present, research suggests that CD86 is a marker of DC activation, and CD83 is a specific marker of DC maturation. DC activation and maturation increase the expression of cell surface molecules CD86 and CD83, otherwise inhibit the differentiation and maturation of DCs, and reduce the expression of cell surface molecules CD86 and CD83 ( 16 – 19 ).…”