Ontogeny of Gut Dendritic Cells in Steady State and Inflamed Settings

描述(申请人提供)：树突状细胞(DC)是高度特化的抗原提呈细胞，存在于所有淋巴组织和非淋巴组织中。在传统的观点中，DC是终末分化的细胞，不断地被一群循环的前体细胞所取代。与这一观点相反，我们最近证明，在小鼠身上，表皮DC也被称为朗格汉斯细胞(LCS)，在静止的皮肤中终生由局部抗辐射增殖前体维持，只有在受伤时才被循环前体所取代。我们还发现，在异基因骨髓移植(allo-BMT)后，宿主耐受的LCS可以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。重要的是，我们发现异体骨髓移植后宿主LCS的持续与严重的皮肤GVHD相关，而供者LCS替代宿主LCS可以改善皮肤GVHD的预后。因此，探索移植物抗宿主病组织靶点的DC动态平衡可能有助于开发治疗这种毁灭性疾病的新策略。除了LC，我们最近还发现，肠道中的DC亚群可以抵抗致命剂量的辐射，这增加了LC可能不是唯一具有抗辐射能力的组织；其他组织可能含有导致GVHD的抗辐射群体。因此，在目标1中，我们将研究DC在肠道中的周转，这是一种特别受GVHD影响的组织。肠道树突状细胞不断地将共生细菌和病原体从肠腔运送到局部淋巴组织，在先天性免疫和获得性免疫中发挥着关键作用。为了面对它们的持续迁移，肠道DC必须被新的细胞取代，但维持肠道DC池的承诺前体的性质仍然难以捉摸。使用新的策略，我们最近已经将循环LC前体表征为循环单核细胞的特定亚群。我们还建立了导致单核细胞成为LC的事件序列，并发现这一过程需要通过CSF-1受体的信号传递(《自然免疫学》出版)。因此，在目标2中，我们建议使用类似的方法来探索稳态下肠道DC的动态平衡，并确定导致肠道DC产生的循环前体。最后，我们发现DC嵌合体的诱导对于预防GVHD至关重要，这使得我们在目标3中确定了在allo-BMT的临床相关模型中重新填充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.