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

糖蛋白CD83属于免疫球蛋白家族，最初被描述为成熟树突状细胞(DC)的标志分子。在活化的B细胞和T细胞上也检测到CD83的表面表达，我们发现CD83在调节性T细胞(Tregs)中高表达，而不是单纯的CD4+T细胞。然而，CD83对T细胞和DC功能的影响仍不清楚。我们先前的研究表明，CD83在CD4+T细胞中的过度表达足以在体外赋予这些细胞免疫抑制活性。值得注意的是，在实验性自身免疫性脑脊髓炎(EAE)中，转移逆转录病毒转导的CD83+T细胞可减少接触性超敏反应(CHS)，降低瘫痪程度。这些数据表明CD83的表达与T细胞的免疫抑制功能有关。为了更好地确定自然表达的CD83的作用，我们建立了一个新的CD83/FLOX转基因小鼠系。通过与各自表达cre的小鼠系交配，我们的CD83Flox/FLOX小鼠代表了一个合适的模型来分析CD83对T细胞和DC的影响。本研究的目的是从CD83-FLOX/FLOX/CD4cre和CD83-FLOX/FIC(Fox-IRES-cre)小鼠分离的CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠和CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠分离的CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠和CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠分离的CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠和CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠分离的CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠和CD83FLOX/FLOX/FIC(Fox-IRES-cre)小鼠的CD11c+树突状细胞(CD11c+DC)的分子和功能表型以及CD83缺陷的DCs的增殖和抑制活性假定的CD83对免疫调节特性的影响将在接触性超敏模型和体内肿瘤移植模型中进行分析。CD83的配体及其作用机制尚不清楚，但CD83与粘膜上皮细胞的同型相互作用已被提出。因此，我们的目标是分析在DC/T细胞相互作用过程中是否发生CD83同型结合，这是否会对各自细胞的表型产生影响，以及哪些信号通路受到影响。为了回答这些问题，我们将利用表达CD83的野生型细胞和从我们新产生的条件CD83缺陷小鼠系中分离出来的CD83缺陷细胞。总之，我们的计划将有助于更好地了解CD83对获得性免疫的影响，并将为靶向CD83是否适合于不同免疫反应的治疗调控提供证据。

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.