The impact of T-cell- and dendritic cell-derived CD83 on immune regulation

• Applicant: Professorin Dr. Wiebke Hansen
• Subject Area: Immunology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280719226

The glycoprotein CD83 belongs to the immunoglobulin superfamiliy and was originally described as a marker molecule for mature dendritic cells (DCs). Surface expression of CD83 was also detected on activated B cells and T cells and we identified CD83 to be highly expressed by regulatory T cells (Tregs) in contrast to naïve CD4+ T cells. However, the impact of CD83 on T cell and DC function still remains unclear. Our previous studies revealed that over-expression of CD83 in CD4+ T cells was sufficient to confer immune-suppressive activity to these cells in vitro. Strikingly, transfer of retrovirally transduced CD83+ T cells resulted in reduced contact hypersensitivity reaction (CHS) and lower paralysis during experimental autoimmune encephalomyelitis (EAE). These data suggest that CD83 expression is involved in the immune-suppressive function of T cells. To better define the role of naturally expressed CD83 we have generated a new CD83flox/flox transgenic mouse line. By breeding with the respective cre-expressing mouse lines our CD83flox/flox mice represent a suitable model to dissect the impact of CD83 specifically in T cells and also DCs. We aim to carefully characterize the molecular and functional phenotype of CD4+ T cells and Foxp3+ Tregs isolated from CD83flox/flox/CD4cre and CD83flox/flox/FIC (Fox-IRES-cre) mice as well as CD11c+ DCs from CD83flox/flox/CD11ccre mice with regard to the expression of activation-, effector function- and/ or Treg-related molecules, cytokines and transcription factors in addition to their proliferative and inhibitory activity or T cell stimulatory capability of CD83-deficient DCs, respectively. The assumed impact of CD83 on immune-regulatory properties will be analyzed in a contact hypersensitivity model and a tumor transplantation model in vivo. The ligand of CD83 and the mechanism by which CD83 exerts its function are not identified yet, but CD83 homotypic interactions of DCs and mucosal epithelial cells have been proposed most recently. Therefore, we aim to analyze whether CD83 homotypic binding occurs during DC/ T cell interaction, if this has an impact on the phenotype of the respective cells and which signaling pathways are affected. To answer these questions we will make use of CD83 expressing wildtype cells and CD83-deficient cells isolated from our newly generated conditional CD83-deficient mouse lines. Overall, our proposed project will help to better understand the impact of CD83 on adaptive immunity and will provide evidence whether targeting of membrane-bound CD83 is a suitable approach for therapeutic modulation of different immune responses.

• DFG Programme: Research Grants