Ontogeny of Gut Dendritic Cells in Steady State and Inflamed Settings

描述（由申请人提供）：树突状细胞（DC）是在所有淋巴和非淋巴组织中发现的高度特化的抗原呈递细胞。在传统观点中，DC是终末分化的细胞，不断被循环前体库取代。与此观点相反，我们最近证明，在小鼠中，表皮DC也称为朗格汉斯细胞（LC），在静止皮肤中的整个生命周期中由局部抗辐射增殖前体维持，并且仅在损伤期间被循环前体取代。我们还发现，宿主抗辐射LC可以在异基因骨髓移植（allo-BMT）后在受体小鼠中持续存在。移植物抗宿主病（GVHD）是异基因骨髓移植后死亡和发病的主要原因。更重要的是，我们发现异基因骨髓移植后宿主LCs的持续存在与严重的皮肤GVHD相关，而供体LCs替代宿主LCs可改善皮肤GVHD结果。因此，探索DC在GVHD组织靶点中的稳态可能有助于开发治疗这种毁灭性疾病的新策略。除了LC之外，我们最近发现肠道中的DC亚群可以抵抗致死剂量的辐射，这提高了LC可能不是唯一具有辐射抗性的可能性;其他组织可能具有导致GVHD的辐射抗性群体。因此，在目标1中，我们将检查肠道中DC的周转，肠道是特别受GVHD影响的组织。肠道DCs能将肠道内的细菌和病原体不断地运送到局部淋巴组织，在先天性免疫和适应性免疫中发挥重要作用。为了应对它们的持续迁移，肠道DC必须被新细胞取代，但维持肠道DC库的定型前体的性质仍然难以捉摸。使用新的策略，我们最近的特点是循环LC前体作为循环单核细胞的一个特定的子集。我们还建立了导致单核细胞成为LC的事件序列，并发现通过CSF-1受体的信号传导是该过程所需的（Nature Immunology出版）。因此，在目标2中，我们提出使用类似的方法来探索稳态下肠道中的DC稳态，并鉴定产生肠道DC的循环前体。最后，我们发现DC嵌合体的诱导对于预防GVHD是至关重要的，这使我们在目标3中确定在临床相关的allo-BMT模型中重新填充DC的循环前体的性质。

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are highly specialized antigen presenting cells found in all lymphoid and non-lymphoid tissues. In the traditional view, DCs are terminally differentiated cells constantly replaced by a pool of circulating precursors. In contrast to this view, we recently demonstrated that in mice, epidermal DCs also called Langerhans cells (LCs) are maintained by local radio-resistant proliferative precursors, throughout life in quiescent skin, and are replaced by circulating precursors only during injuries. We have also discovered that host radio-resistant LCs can persist in recipient mice after allogeneic bone marrow transplant (allo-BMT). Graft versus host disease (GVHD) is a major cause of mortality and morbidity after allo-BMT. Importantly, we found that persistence of host LCs after allo-BMT correlates with severe skin GVHD, while replacement of host LCs by donor LCs improves skin GVHD outcome. Therefore, exploring DC homeostasis in a tissue target of GVHD may help develop new strategies for the treatment of this devastating disease. In addition to LCs, we recently discovered that a subset of DCs in the gut can resist lethal doses of radiation, raising the possibility that LCs may not be unique in being radio-resistant; other tissues may harbor radio- resistant populations that contribute to GVHD. Thus, in aim 1, we will examine the turnover of DCs in the gut, a tissue that is particularly affected by GVHD. Gut DCs constantly transport commensal bacteria and pathogens from the luminal intestine to local lymphoid tissues, playing a critical role in innate and adaptive immunity. To face their continuous migration, gut DCs must be replaced with new cells, but the nature of the committed precursor that maintains the gut DC pool remains elusive. Using novel strategies, we have recently characterized the circulating LC precursor as being a specific subset of circulating monocytes. We also established the sequence of events that leads a monocyte to become a LC and discovered that signaling through the receptor for CSF-1 is required for this process (Nature Immunology in press). Therefore in aim 2, we propose to use similar approaches to explore DC homeostasis in the gut in the steady state and identify the circulating precursor that gives rise to intestinal DCs. Finally, our finding that induction of DC chimerism is critical to prevent GVHD leads us, in aim 3, to determine the nature of the circulating precursor that repopulates DCs in a clinically relevant model for allo-BMT.