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.
Simone Dertschnig, Pamela Evans, Pedro Santos e Sousa, Teresa Manzo, Ivana R. Ferrer, Hans J. Stauss, Clare L. Bennett, Ronjon Chakraverty