One-two punch injury to tolerance mechanisms in graft-versus-host disease
Léolène J. Carrington, Ivan Maillard
Léolène J. Carrington, Ivan Maillard
Published March 9, 2020
Citation Information: J Clin Invest. 2020;130(4):1625-1628. https://doi.org/10.1172/JCI136139.
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Commentary

One-two punch injury to tolerance mechanisms in graft-versus-host disease

Abstract

Chronic graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic cell transplantation that resembles autoimmunity, with unclear pathogenesis and few effective therapeutic options. In this issue of the JCI, Dertschnig et al. used mouse models to investigate the basis of T cell autoreactivity following GVHD. Notably, GVHD caused irreversible damage to a population of tolerogenic stromal cells that display peripheral tissue–restricted antigens in lymph nodes, which impaired their capacity to purge and suppress autoreactive T cells. Together with damage to central tolerance mechanisms in the thymus, these findings outline a critical one-two punch injury that profoundly disrupts immune tolerance in this devastating disease.

Authors

Léolène J. Carrington, Ivan Maillard

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Figure 1

Model of impaired tolerance in GVHD pathogenesis.

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Model of impaired tolerance in GVHD pathogenesis. Acute GVHD simultaneou...
Acute GVHD simultaneously damages nonhematopoietic cells enforcing central and peripheral tolerance in the thymus and lymph nodes. In the thymus, mTECs ectopically express a broad range of tissue-restricted antigens under the control of the autoimmune regulator AIRE. mTECs promote the negative selection of autoreactive T cells and development of central tolerance. In the periphery, lymph node FRCs also show promiscuous expression of tissue-restricted antigens and facilitate the suppression of mature autoreactive T cells, thereby maintaining peripheral tolerance. Acute GVHD targets both mTECs in the thymus and FRCs in lymph nodes, thereby creating a dangerous situation in which large numbers of autoreactive T cells are left to sustain tissue damage during chronic GVHD. TRA, tissue-restricted antigen; GVHD, graft-versus-host disease; mTECs, medullary thymic epithelial cells; AIRE, autoimmune regulator; FRCs, fibroblastic reticular cells.