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

糖蛋白CD83属于免疫球蛋白超家族，最初被描述为成熟树突状细胞（DCs）的标记分子。在活化的B细胞和T细胞上也检测到CD83的表面表达，与naïve CD4+ T细胞相比，我们发现CD83在调节性T细胞（Tregs）中高表达。然而，CD83对T细胞和DC功能的影响尚不清楚。我们之前的研究表明，CD4+ T细胞中CD83的过表达足以在体外赋予这些细胞免疫抑制活性。引人注目的是，在实验性自身免疫性脑脊髓炎（EAE）期间，逆转录病毒转导的CD83+ T细胞的转移导致接触超敏反应（CHS）的减少和瘫痪的减少。这些数据表明CD83的表达参与了T细胞的免疫抑制功能。为了更好地定义自然表达的CD83的作用，我们产生了一个新的CD83flox/flox转基因小鼠系。通过与各自的crec表达小鼠系杂交，我们的CD83flox/flox小鼠代表了一个合适的模型，可以分析CD83在T细胞和dc中的特异性影响。我们的目标是仔细表征CD83flox/flox/CD4cre和CD83flox/flox/FIC （Fox-IRES-cre）小鼠中分离的CD4+ T细胞和Foxp3+ Tregs的分子和功能表型，以及CD83flox/flox/CD11ccre小鼠中CD11c+ dc的激活、效应功能和/或treg相关分子、细胞因子和转录因子的表达，以及它们对cd83缺陷dc的增殖和抑制活性或T细胞刺激能力。我们将在体内接触性超敏反应模型和肿瘤移植模型中分析CD83对免疫调节特性的假设影响。CD83的配体和CD83发挥其功能的机制尚未确定，但CD83与dc和粘膜上皮细胞的同型相互作用最近被提出。因此，我们的目的是分析DC/ T细胞相互作用过程中CD83同型结合是否发生，这是否对各自细胞的表型有影响，以及哪些信号通路受到影响。为了回答这些问题，我们将利用从我们新生成的条件CD83缺陷小鼠系中分离的CD83表达野生型细胞和CD83缺陷细胞。总的来说，我们提出的项目将有助于更好地了解CD83对适应性免疫的影响，并将提供证据，证明靶向膜结合CD83是否是治疗性调节不同免疫反应的合适方法。

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.