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

肥大细胞（MCs）被认为是ige介导的I型过敏反应的效应细胞。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导致MCs和树突状细胞（dc）之间的动态通信，两者都是组织常驻前哨细胞。炎症性损伤后，dc积极吞噬完整的MC颗粒，由MC脱颗粒排出。含有MC颗粒的DCs显示出高度增强的成熟和向排水的迁移，以及增强的T细胞启动能力。相反，在离开发炎的皮肤之前，dc与mc进行了有针对性的、持久的相互作用。这些先天突触样接触最终导致包括MHC II类复合物在内的蛋白质物质转移到MCs，从而使MCs具备抗原递呈能力。由于MCs在炎症部位保持静止，因此dc将MCs与MHCII复合物“交叉装扮”可能确保效应T细胞重新激活，从而返回皮肤。在该项目中，我们旨在确定dc -MC通信的分子机制，并破译dc对MC功能的MC教育的功能后果。此外，我们的目标是确定MCs如何促进效应T细胞的再激活，这些效应T细胞已经被引流LN并回到发炎的皮肤，特别是MHCII复合物被dc交叉修饰的影响。由于MCs提供广泛的促炎介质和免疫抑制介质，因此MCs向皮肤归巢效应T细胞的抗原呈递可能具有特定的特征，并导致不同的T细胞极化和细胞因子反应。因此，dc对MC与MHCII复合物的交叉修饰程度可能与T细胞驱动炎症的振幅和质量的不同调节有关。因此，修改MCs和dc之间的通讯可能是一种有前途的创新策略，可以治疗干预T细胞驱动的炎症性疾病。

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.