Acute graft-versus-host disease (GVHD) is initially triggered by alloreactive T cells, which damage peripheral tissues and lymphoid organs. Subsequent transition to chronic GVHD involves the emergence of autoimmunity although the underlying mechanisms driving this process are unclear. Here, we tested the hypothesis that acute GVHD blocks peripheral tolerance of autoreactive T cells by impairing lymph node (LN) display of peripheral tissue-restricted antigens (PTA). At the initiation of GVHD, LN fibroblastic reticular cells (FRC) rapidly reduced expression of genes regulated by DEAF1, an Autoimmune Regulator-like transcription factor required for intra-nodal expression of PTA. Subsequently, GVHD led to the selective elimination of the FRC population, and blocked the repair pathways required for its regeneration. We used a transgenic mouse model to show that the loss of presentation of an intestinal PTA by FRC during GVHD resulted in the activation of auto-aggressive T cells and gut injury. Finally, we show that FRC normally expressed a unique PTA gene signature that was highly enriched for genes expressed in the target organs affected by chronic GVHD. In conclusion, acute GVHD damages and prevents repair of the FRC network, thus disabling an essential platform for purging auto-reactive T cells from the repertoire.

中文翻译：

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移植物抗宿主病减少了组织受限的自身抗原的淋巴结显示，并促进了自身免疫。

急性移植物抗宿主病（GVHD）最初是由同种异体反应性T细胞触发的，它会损伤周围组织和淋巴器官。尽管尚不清楚驱动该过程的潜在机制，但随后向慢性GVHD的转化涉及自身免疫的出现。在这里，我们测试了一种假说，即急性GVHD通过损害外周组织限制性抗原（PTA）的淋巴结（LN）显示来阻断自身反应性T细胞的外周耐受性。在开始GVHD时，LN纤维母细胞网状细胞（FRC）迅速降低了由DEAF1调控的基因的表达，DEAF1是结内表达PTA所需的自体免疫调节因子样转录因子。随后，GVHD导致选择性消除FRC种群，并阻断了其再生所需的修复途径。我们使用转基因小鼠模型显示，在GVHD期间FRC失去肠道PTA的表达会导致自激性T细胞活化和肠道损伤。最后，我们显示FRC通常表达独特的PTA基因签名，该签名对于受慢性GVHD影响的靶器官中表达的基因高度丰富。总之，急性GVHD会损害并阻止FRC网络的修复，从而使从库中清除自身反应性T细胞的重要平台失灵。