Abstract
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 (PTAs). At the initiation of GVHD, LN fibroblastic reticular cells (FRCs) rapidly reduced expression of genes regulated by DEAF1, an autoimmune regulator-like transcription factor required for intranodal expression of PTAs. 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 FRCs during GVHD resulted in the activation of autoaggressive T cells and gut injury. Finally, we show that FRCs 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 autoreactive T cells from the repertoire.
Highlights
The success of allogeneic hematopoietic stem cell transplantation is limited by the occurrence of graft-versus-host disease (GVHD), an acute inflammatory process triggered by the influx of alloreactive effector T cells into barrier surface tissues and lymphoid organs [1]
Based on a comparison of peripheral tissue–restricted antigens (PTAs) gene expression between the different lymph node (LN) stromal cell subsets (Figure 7B), we identified a list of 356 putative fibroblastic reticular cells (FRCs)-specific PTA genes based on greater than 3-fold higher expression and an adjusted P value of 0.05 or less compared with the other LN stromal subsets
Of note, when we evaluated in which tissues each of these genes was expressed, we found that 246 of 356 (69.1%) of the PTA genes were expressed in known target tissues affected by chronic GVHD; this same level of enrichment was not observed in a randomly selected set of 356 non–FRC-specific PTA genes expressed in LN stromal cells where 187 of 356 (52.2%) genes were expressed in chronic GVHD target tissues (P < 0.0001, Fisher’s exact test; Figure 7C)
Summary
The success of allogeneic hematopoietic stem cell transplantation is limited by the occurrence of graft-versus-host disease (GVHD), an acute inflammatory process triggered by the influx of alloreactive effector T cells into barrier surface tissues (primarily skin and gut) and lymphoid organs [1]. Medullary thymic epithelial cells (mTECs) are sensitive to immune injury in GVHD [9]; these stromal cells display peripheral tissue–restricted antigens (PTAs) through a process that requires the transcription factor autoimmune regulator (AIRE) and are normally required for the negative selection of self-reactive thymocytes [12]. In the T cell zone and are well positioned to present PTAs to naive T cells in the steady state [19] In contrast to their inhibitory functions in regulating T cell autoreactivity to PTAs, FRCs have recently been shown to initiate T cell reactivity to alloantigens in GVHD [20]. Lack of RORγt+ LTi-like cells at the time of acute LCMV infection was shown to impair FRC network restoration [26] Whether such a repair process is operative in the context of FRC injury in GVHD is not known.
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