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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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Research Article Autoimmunity

Graft-versus-host disease reduces lymph node display of tissue-restricted self-antigens and promotes autoimmunity

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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 4

Acute GVHD blocks stromal reorganization and repair of the FRC network.

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Acute GVHD blocks stromal reorganization and repair of the FRC network.
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(A) Heatmap depicting relative expression values of specific genes involved in a stromal reorganization program. Relative expression is shown in FRCs isolated from untransplanted mice, or from TCDBM recipients and TCDBM+T recipients 7 days following F→M BMT. (B) Absolute numbers of host and donor LTi cells were evaluated at indicated time points in the presence or absence of acute GVHD following F→M BMT. Dotted line indicates mean absolute numbers of LTi cells in untreated mice. Statistical analysis is of donor cells only. Data derived from 3 independent experiments. (C) Surface expression of VCAM1 and ICAM1 on CD45–CD31–gp38+ LN stromal cells in untransplanted controls (gray) and BMT recipients of TCDBM alone (blue) or TCDBM+T (red) at indicated time points after F→M BMT. Summary data depicting MFI of VCAM1 within the CD45–CD31–gp38+ population in TCDBM or TCDBM+T recipients is shown below the respective flow cytometry plots (data derived from 6 independent experiments). (D) [Rorc WT→Rorc WT] or [Rorc KO→Rorc WT] chimeras were analyzed for the presence of LTi cells within LNs at 8 weeks after primary BMT. Plots depict expression of CD127 and RORγt among lineage–CD117+ cells. Percentage and absolute numbers of FRCs is shown for [Rorc WT→Rorc WT] and [Rorc KO→Rorc WT] chimeras at 8 weeks after primary BMT (data derived from 3 independent experiments). (E) Eight weeks after the first BMT, [Rorc WT→Rorc WT] and [Rorc KO→Rorc WT] chimeras were reirradiated and underwent secondary F→M BMT with either TCDBM alone or TCDBM+T to induce acute GVHD. Plots show percentage (left) and absolute numbers (right) of FRCs analyzed at 2 weeks after the second transplantation (data derived from 2 independent experiments). Data represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 by Mann-Whitney U test (B and C) or Kruskal-Wallis ANOVA (E).

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