Control of the homeostatic regulatory T cell pool by RelB expression in steady state migratory dendritic cells

通过稳态迁移树突状细胞中的 RelB 表达控制稳态调节 T 细胞库

• 批准号: 233384519
• 负责人: Professor Dr. Manfred Lutz
• 金额: --
• 依托单位: Institut für Virologie und Immunbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/233384519?language=en
• 关键词: Control; homeostatic; regulatory; cell; pool

Interactions of dendritic cells (DCs) with regulatory T cells (Tregs) play a key role for immune tolerance by controlling Treg induction, maintenance and proliferation. Using a transgenic mouse expressing ovalbumin (OVA) as a neo-self-antigen under the keratin-5 promoter in the epidermis (K5-mOVA) and OVA-specific CD4+ T cell receptor transgenic mice (OT-II), we found previously that OVA-self-antigen presentation in the draining lymph nodes strictly depends on the transport by steady state migratory DCs (ssmDCs) and leads to conversion of naive CD4+ T cells into CD4+ Foxp3+ Tregs. Using mice with genetic deficiencies for the NF-kB/Rel transcription factor family members RelB, p52 or p50 we could show that the alternative NF-kB signaling pathway through RelB/p52 controls the migration of ssmDCs and thereby Tregs.To gain deeper insights into the specific role of the RelB transcription factor for ssmDCs, Tregs and peripheral tolerance, we started now to investigate mice that specifically lack RelB in CD11c+ DCs (RelBDCko). This could achieved by crossing Cre recombinase expressing mice under the DC-specific promoter CD11c (CD11c-Cre) with mice where both RelB alleles are flanked by loxP sites (RelBfl/fl). Our preliminary data indicate that RelBDCko mice appear largely normal. However, they show increased frequencies of ssmDCs in peripheral lymph nodes, of CD4+ Foxp3+ Tregs and of an IL-2-producing (presumably IL-7-dependent) CD4+ CD44high T cell subset in thymus, lymph nodes and spleen. In this proposal we would like to study the functional relations between these three cell types. We hypothesize that in the absence of RelB in ssmDCs the binding partner p52 forms alternative conjugates with other NF-kB/Rel family members that we will identify. Then we want to test whether the IL-2 or IL-7 release is altered in DC or T cells of RelBDCko mice and how RelB-deficiency influences the ssmDC turnover. By using the K5-mOVA/OT-II system we want to study the impact of RelB-deficiency by DCs on natural and inducible Treg subsets and whether it requires antigen-specificity. We will ask which surface receptors or the IL-2/IL-7 cytokines contribute to the increased steady state frequencies of Treg and CD4+ CD44high T cells in RelBDCko mice. Finally we want to determine if the tolerance threshold of RelBDCko mice with elevated levels of Tregs is increased after induction of allergy or autoimmunity.Together this project will contribute to answer the question how steady state levels of Tregs are adjusted in vivo and how these manipulations of Treg populations influence susceptibility against allergy or autoimmunity.

树突状细胞（DCs）与调节性T细胞（Treg）的相互作用通过控制Treg的诱导、维持和增殖在免疫耐受中起关键作用。使用在表皮中在角蛋白-5启动子下表达卵清蛋白（OVA）作为新自身抗原的转基因小鼠（K5-mOVA）和OVA特异性CD4 + T细胞受体转基因小鼠（OT-II），我们先前发现，引流淋巴结中的OVA自身抗原呈递严格依赖于稳态迁移性DC（ssmDC）的转运，并导致初始CD4 + T细胞转化为CD4 + Foxp3 + T细胞。你好使用具有NF-kB/Rel转录因子家族成员RelB、p52或p50的遗传缺陷的小鼠，我们可以表明通过RelB/p52的替代NF-kB信号传导途径控制ssmDC的迁移，从而控制TclD。我们现在开始研究在CD11c + DC中特异性缺乏RelB的小鼠（RelBDCko）。这可以通过将在DC特异性启动子CD11c下表达Cre重组酶的小鼠（CD11c-Cre）与其中两个RelB等位基因侧接loxP位点的小鼠（RelBfl/fl）杂交来实现。我们的初步数据表明，RelBDCko小鼠似乎基本正常。然而，他们显示外周淋巴结中ssmDC的频率增加，胸腺、淋巴结和脾脏中CD4 + Foxp3 + T细胞和产生IL-2（推测为IL-7依赖性）的CD4 + CD44high T细胞亚群的频率增加。在这个建议中，我们想研究这三种细胞类型之间的功能关系。我们假设在ssmDC中不存在RelB的情况下，结合伴侣p52与我们将鉴定的其他NF-κ B/Rel家族成员形成替代缀合物。然后，我们想测试RelB DCko小鼠的DC或T细胞中IL-2或IL-7的释放是否改变，以及RelB缺乏如何影响ssmDC的周转。通过使用K5-mOVA/OT-II系统，我们希望研究DC的RelB缺陷对天然和诱导型Treg亚群的影响以及它是否需要抗原特异性。我们将询问哪些表面受体或IL-2/IL-7细胞因子有助于RelBDCko小鼠中Treg和CD4 + CD44high T细胞的稳态频率增加。最后，我们想确定是否有升高水平的TCLs的RelBDCko小鼠的耐受性阈值增加后，诱导过敏或自身免疫。这个项目将有助于回答的问题，如何稳态水平的TCLs在体内调节，以及如何这些Treg群体的操作影响对过敏或自身免疫的易感性。