Defining mast cell functions in effector T cell activation at the peripheral site of inflammation and the relevance of MHCII cross-dressing by dendritic cells

定义肥大细胞在炎症外周部位效应 T 细胞激活中的功能以及树突状细胞 MHCII 异装的相关性

• 批准号: 431767831
• 负责人: Professorin Dr. Anne Dudeck
• 金额: --
• 依托单位: Institut für Molekulare und Klinische Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/431767831?language=en
• 关键词: Defining; mast; cell; functions; effector

Mast cells (MCs) are best known as effector cells of IgE-mediated type I allergic responses. However, there is increasing evidence for important MC functions in acute host defense and in the induction of adaptive responses. Using longitudinal intravital multiphoton microscopy, we recently found that skin inflammation results in a dynamic communication between MCs and dendritic cells (DCs), both tissue resident sentinel cells. DCs actively engulfed intact MC granules exocytosed by MC degranulation upon inflammatory insult. DCs bearing MC granules showed a highly enhanced maturation and migration to draining LNs, and a boosted T cell priming capacity. Conversely, before leaving the inflamed skin, DCs executed targeted and long-lasting interactions with MCs. These innate synapse-like contacts ultimately culminated in the transfer of protein material including MHC class II complexes to MCs thereby equipping MCs with antigen presentation capacity. Since MCs remain stationary at the site of inflammation, the "cross-dressing" of MCs with MHCII complexes by DCs may ensure the re-activation of effector T cells that home back to the skin. In the proposed project, we aim to identify the molecular mechanisms of the DC-to-MC communication and to decipher the functional consequence of MC education by DCs on MC functions. Moreover, we aim to determine how MCs contribute to the re-activation of effector T cells that have been primed in draining LN and home back to the inflamed skin, and in particular, the impact of MHCII complexes cross-dressed by DCs. Since MCs provide a broad spectrum of pro-inflammatory but also immunosuppressive mediators, antigen presentation to skin homing effector T cells by MCs may have a specific signature and result in distinct T cell polarization and cytokine response. Consequently, the extent of MC cross-dressing with MHCII complexes by DCs may correlate with distinct modulations of the amplitude and quality of T cell-driven inflammation. Therefore, modifying the communication between MCs and DCs may be a promising and innovative strategy to therapeutically intervene T cell-driven inflammatory diseases.

肥大细胞（MC）是IgE介导的I型变态反应的效应细胞。然而，越来越多的证据表明MC在急性宿主防御和诱导适应性反应中具有重要的功能。使用纵向活体多光子显微镜，我们最近发现，皮肤炎症的结果在MC和树突状细胞（DC），组织驻地哨兵细胞之间的动态通信。DCs主动吞噬炎性损伤时MC脱粒所排出的完整MC颗粒。携带MC颗粒的DC表现出高度增强的成熟和向引流淋巴结的迁移，以及增强的T细胞引发能力。相反，在离开发炎的皮肤之前，DC与MC进行靶向和持久的相互作用。这些先天性突触样接触最终导致包括MHC II类复合物的蛋白质物质转移到MC，从而使MC具有抗原呈递能力。由于MC在炎症部位保持静止，DC对MC与MHCII复合物的“交叉修饰”可以确保返回皮肤的效应T细胞的再活化。在拟议的项目中，我们的目标是确定的DC到MC通信的分子机制，并破译MC教育的功能性后果的DC对MC功能。此外，我们的目标是确定MC如何有助于重新激活效应T细胞，这些效应T细胞已经在引流LN中启动并返回发炎的皮肤，特别是DC交叉修饰的MHCII复合物的影响。由于MC提供广谱的促炎介质，但也提供免疫抑制介质，因此MC对皮肤归巢效应T细胞的抗原呈递可能具有特异性特征，并导致不同的T细胞极化和细胞因子应答。因此，MC cross-dressing与MHCII复合物的DC的程度可能与T细胞驱动的炎症的幅度和质量的不同调节相关。因此，修饰MC和DC之间的通讯可能是治疗性干预T细胞驱动的炎性疾病的有前途的和创新的策略。