CD83

It is not clear what ligands interact with CD83, but membrane-bound CD83 may homotypically interact with the soluble form, suggesting autocrine immune regulation.[11] However, it contrasts with differences between the single expression of soluble CD83 on monocytes and membrane-bound CD83 on activated dendritic cells seems also as their good marker.[12] Soluble CD83 also binds to CD154, leading to T helper type 2 lymphocyte apoptosis by suppression of Bcl-2 inhibitors.[13]

The development of thymocytes during the positive-selection stage may be guided by CD83 expression on cortical thymic epithelial cells (cTECs). CD4⁺CD8⁺ double-positive thymocytes surrounded by specially differentiated cTECs called thymic nurse cells are tested for function of their αβ T cell receptor (TCR); a nonreactive TCR leads to thymocyte death by neglect. Successful rearrangement of a reactive TCR supports survival and restriction of expression to CD4 or CD8 alone on single-positive thymocytes, depending on the ability to recognize MHC II or MHC I, respectively. Upregulation of MHC II turnover on thymic nurse cells by CD83 may enlarge the population of CD4⁺ single-positive thymocytes.[14][15]

Role of CD83 in tolerance establishment balance

T regulatory cells (T_reg cells) are present in two major populations: thymically induced and peripherally induced T_reg cells. All T_reg cells express the Foxp3 transcription factor, establishing their suppressive phenotype. Foxp3 expression is not affected by loss of CD83 in a CD83 knockout mouse. In contrast, CD83 seems important for peripheral T_reg cell induction, as suggested by reduction of this population in a conditional knockout mouse lacking CD83 specifically in T_reg cells, which results in a proinflammatory phenotype.[16]

CD83 deficiency also results in an imbalances in effector function of T_reg cells, as decreased expression of the T helper type 2 cell transcription factor GATA3 is also important for ST2 production.[17]

Activated T_reg cells produce large amounts of soluble CD83, leading to downregulation of IRAK-1 at inflamed sites, downregulation of toll-like receptor signaling, and switching of inflammatory signals to tolerance establishment.[18]

CD83 expression is a marker for mature dendritic cells.[12] CD83 stabilizes MHC II on membrane by antagonizing MARCH E3 ubiquitin ligases. A MARCH1 knockout mouse shows accumulation of MHC II, which leads to reduced CD4⁺ T lymphocyte activation and reduced IL-12 production.[19] Conversely, a CD83 knockout mouse shows a reduction of MHC II and CD86, better response to bacterial infection, and higher production of IL-12 than in the wild type. CD83 seems to be an important regulator of dendritic cell phenotype and MHC II turnover, mediated by CD83-dependent endosome processing.[20]

CD83 expression correlates with rate of activation of B lymphocytes and it is under control of the B cell receptor, CD40, or Toll-like receptor activation, as in other lymphocytes, where CD83 is expressed upon stimulation. A CD83 knockout mouse shows upregulated proliferation of B lymphocytes, suggesting that CD83 acts as a brake on proliferation.[21] CD83 does not affect affinity maturation of antibodies, but its deficiency enhances immunoglobulin E class switching, suggesting that CD83 may be involved in allergy development and could be a therapeutic target for allergy treatment.[22]