Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease.
Peripheral tissues reprogram CD8+ T cells for pathogenicity during graft-versus-host disease.
复制标题
外周组织重新编程 CD8 T 细胞，使其在移植物抗宿主病期间具有致病性。
DOI：
10.1172/jci.insight.97011
复制
发表时间：
2018
期刊：
影响因子：
8
通讯作者：
Santos E Sousa P
中科院分区：
文献类型：
--
作者：
Santos E Sousa P
移植物抗宿主病(GVHD)是供者来源的效应T细胞(TE)外周组织涌入异基因干细胞移植后引起的一种危及生命的并发症。目前的治疗策略依赖于靶向全身T细胞；然而，编程TE成为致病和触发损伤的指令的确切位置和性质尚不清楚。因此，我们使用加权基因共表达网络分析来构建GVHD进化过程中TE分化的无偏空间图谱，并根据位置确定小鼠和人类效应器程序的广泛差异。在受影响的器官中，效应器编程的特殊性并不是由于T细胞受体谱系的变化或最佳激活TE的选择造成的。取而代之的是，TE被靶器官中的组织自主机制重新编程，以实现与淋巴结内启动的功能高度不同的特定部位的促炎功能。在皮肤中，我们将基于相关性的网络与基于模块的差异表达分析相结合，表明朗格汉斯细胞为Notch依赖的T细胞基因簇提供了原位指令，该基因簇对于触发局部损伤至关重要。因此，GVHD中TE致病性的主要决定因素是最终的目的地，强调了靶向器官特异性方法的必要性，以阻断免疫病理，同时避免全球免疫抑制。
Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ–specific approaches to block immunopathology while avoiding global immune suppression.