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

糖蛋白CD 83属于免疫球蛋白超家族，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CD 83的表面表达，并且我们鉴定出与幼稚的CD 4 + T细胞相比，CD 83由调节性T细胞（TCD 4）高度表达。然而，CD 83对T细胞和DC功能的影响仍不清楚。我们以前的研究表明，CD 4 + T细胞中CD 83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，逆转录病毒转导的CD 83 + T细胞的转移导致实验性自身免疫性脑脊髓炎（EAE）期间接触性超敏反应（CHS）降低和瘫痪降低。这些数据表明，CD 83表达参与T细胞的免疫抑制功能。为了更好地定义天然表达的CD 83的作用，我们已经产生了新的CD 83 flox/flox转基因小鼠系。通过与各自的表达cre的小鼠系繁殖，我们的CD 83 flox/flox小鼠代表了一种合适的模型，以剖析CD 83特异性地在T细胞和DC中的影响。我们的目的是仔细表征从CD 83 flox/flox/CD 4cre和CD 83 flox/flox/FIC分离的CD 4 + T细胞和Foxp 3 + T细胞的分子和功能表型。（Fox-IRES-cre）小鼠以及来自CD 83 flox/flox/CD 11 ccre小鼠的CD 11 c + DC的活化、效应功能和/或Treg相关分子的表达，细胞因子和转录因子，以及它们的增殖和抑制活性或CD 83缺陷型DC的T细胞刺激能力。将在接触性超敏反应模型和体内肿瘤移植模型中分析CD 83对免疫调节特性的假设影响。CD 83的配体和发挥其功能的机制尚未确定，但最近提出了DC和粘膜上皮细胞之间的CD 83同型相互作用。因此，我们的目标是分析在DC/ T细胞相互作用期间是否发生CD 83同型结合，如果这对相应细胞的表型有影响，以及哪些信号通路受到影响。为了回答这些问题，我们将利用表达CD 83的野生型细胞和从我们新产生的条件性CD 83缺陷小鼠系分离的CD 83缺陷细胞。总的来说，我们提出的项目将有助于更好地了解CD 83对适应性免疫的影响，并将提供证据，证明靶向膜结合CD 83是否是一种合适的方法，用于不同的免疫反应的治疗调节。

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.