The Extracellular Domain of CD83 Inhibits Dendritic Cell–mediated T Cell Stimulation and Binds to a Ligand on Dendritic Cells

Abstract

CD83 is an immunoglobulin (Ig) superfamily member that is upregulated during the maturation of dendritic cells (DCs). It has been widely used as a marker for mature DCs, but its function is still unknown. To approach its potential functional role, we have expressed the extracellular Ig domain of human CD83 (hCD83ext) as a soluble protein. Using this tool we could show that immature as well as mature DCs bind to CD83. Since CD83 binds a ligand also expressed on immature DCs, which do not express CD83, indicates that binding is not a homophilic interaction. In addition we demonstrate that hCD83ext interferes with DC maturation downmodulating the expression of CD80 and CD83, while no phenotypical effects were observed on T cells. Finally, we show that hCD83ext inhibits DC-dependent allogeneic and peptide-specific T cell proliferation in a concentration dependent manner in vitro. This is the first report regarding functional aspects of CD83 and the binding of CD83 to DCs.

CD83 Expression in CD4+ T Cells Modulates Inflammation and Autoimmunity

“…However, stimulation of naive T cells in the presence of supernatants from CD83-transduced T cell cultures had no significant effect on the proliferative capacity (data not shown) as it was described for sCD83 (20,24,25). Additionally, CD83-transduced T cells and CD4 ϩ CD25 ϩ Treg cells lost their in vitro suppressive capacity in the absence of cell-cell contact (Fig.…”

“…Additionally, we have recently shown that inhibition of CD83 expression on DCs by CD83-specific small interfering RNAs leads to a reduced DC-mediated T cell stimulation, indicating that on DCs the membranebound form of CD83 acts as a costimulatory molecule (49). Expression of the undefined CD83 ligand (CD83L) has been suggested on DCs (20) and, recently, on activated CD8 ϩ as well as CD4 ϩ T lymphocytes (49). CD83L was expressed on activated T cells only upon stimulation through CD3/CD28 but not CD3 alone, suggesting that CD83L only functions when T cells are activated in the presence of costimulatory signals provided by CD83 ϩ APCs (50).…”

“…This soluble form of CD83 is also present at elevated levels in a number of hematological disorders, including patients with chronic lymphocytic leukemia and mantle cell lymphoma (19). Lechmann and colleagues reported that the extracellular Ig domain of human CD83 blocked the DC-mediated proliferation of allogeneic as well as specific CTLs in vitro (20). Additionally, in the experimental autoimmune encephalomyelitis (EAE) mouse model, injections of sCD83 prevented the disease-associated paralysis under prophylactic as well as therapeutic settings in vivo (21).…”

Phosphorylation of the HuR ligand APRIL by casein kinase 2 regulates CD83 expression

“…Although its exact function is still unknown, various independent studies using soluble forms of CD83 or employing CD83-specific RNA interference provided evidence that this surface molecule is required for efficient DC-mediated T-cell activation [14][15][16][17]19]. Furthermore, it has been shown that CD4 1 single-positive thymocyte development is impaired in CD83 (CD83 À/À ) knockout mice, resulting in pronounced reduction of peripheral CD4 1 T cells [44].…”

“…Moreover, a soluble form of CD83 is detectable at low levels in sera derived from healthy individuals, whereas in contrast, elevated levels are present in patients suffering from certain hematological malignancies [8,11]. Notwithstanding the fact that accumulating experimental evidence suggests that CD83 plays an important functional role in the regulation of DCmediated T-cell-specific immune response [12][13][14][15][16][17][18][19], the exact function of CD83 remains poorly understood [20][21][22]. Nevertheless, various disease-related findings suggest that CD83 holds great potential for future therapeutic application [23].…”