Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity
Simone Dertschnig, … , Clare L. Bennett, Ronjon Chakraverty
Simone Dertschnig, … , Clare L. Bennett, Ronjon Chakraverty
Published January 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1896-1911. https://doi.org/10.1172/JCI133102.
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Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity

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.

Authors

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

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Figure 5

OVA-specific OT-I T cells fail to be purged from the periphery of iFABPtOVA mice with acute GVHD.

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OVA-specific OT-I T cells fail to be purged from the periphery of iFABPt...
(A) Murine transplantation model to investigate peripheral deletion of self-reactive T cells. Acute GVHD was induced in iFABPtOVA male BMT recipients by cotransfer of female TCDBM and Mh CD8+ T cells. No-GVHD controls received TCDBM alone. Male B6 recipients undergoing F→M BMT with or without acute GVHD served as further controls. Six weeks after BMT, 1 × 106 OT-I T cells were transferred and mice were analyzed after 16 days (data derived from 8 independent experiments). (B) Weight change in recipient mice after OT-I T cell transfer is shown as percentage of initial body weight (defined as time point of OT-I transfer). (C) Flow cytometry plots depict surface expression of CD45.1 and Thy1.1 among CD8+ T cells (OT-I T cells are identified as CD45.1+Thy1.1–; Mh T cells are identified as CD45.1+Thy1.1+). Frequencies of OT-I T cells among total live cells in MLNs and the IEL are summarized in dot plots (right panel). (D) Absolute numbers of OT-I T cells in MLNs and the IEL (data derived from 7 independent experiments). (E) Flow cytometry plots depict intracellular IFN-γ expression among CD8+CD45.1+ OT-I T cells in MLNs and the IEL. Percentage of IFN-γ+ OT-I T cells is summarized in dot plots (right panel). (F) Absolute numbers of IFN-γ+ OT-I T cells in MLNs and the IEL (data derived from 8 independent experiments). (G and H) IFN-γ secretion was measured in acute GVHD+ recipients in the absence or presence of donor-derived CD11c+ DCs. Percentage (G) and absolute numbers (H) of IFN-γ+ OT-I T cells are shown for MLNs and the IEL (data derived from 3 independent experiments). Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by Mann-Whitney U test (C–F) or Kruskal-Wallis ANOVA (B, G, and H).