Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease

Laëtitia Le Texier, Katie E Lineburg, Benjamin Cao, Cameron McDonald-Hyman, Lucie Leveque-El Mouttie, Jemma Nicholls, Michelle Melino, Blessy C Nalkurthi, Kylie A Alexander, Bianca Teal, Stephen J Blake, Fernando Souza-Fonseca-Guimaraes, Christian R Engwerda, Rachel D Kuns, Steven W Lane, Michele Teng, Charis Teh, Daniel Gray, Andrew D Clouston, Susan K NilssonBruce R Blazar, Geoffrey R Hill, Kelli P A MacDonald

Research output: Contribution to journalArticle

Abstract

Regulatory T cells (Tregs) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Tregs result in diseases such as autoimmunity, allergy, malignancy, and graft-versus-host disease (GVHD), a serious complication of allogeneic stem cell transplantation (SCT). We recently reported increased expression of autophagy-related genes (Atg) in association with enhanced survival of Tregs after SCT. Autophagy is a self-degradative process for cytosolic components that promotes cell homeostasis and survival. Here, we demonstrate that the disruption of autophagy within FoxP3(+) Tregs (B6.Atg7(fl/fl)-FoxP3cre(+) ) resulted in a profound loss of Tregs, particularly within the bone marrow (BM). This resulted in dysregulated effector T cell activation and expansion, and the development of enterocolitis and scleroderma in aged mice. We show that the BM compartment is highly enriched in TIGIT(+) Tregs and that this subset is differentially depleted in the absence of autophagy. Moreover, following allogeneic SCT, recipients of grafts from B6.Atg7(fl/fl)-FoxP3cre(+) donors exhibited reduced Treg reconstitution, exacerbated GVHD, and reduced survival compared with recipients of B6.WT-FoxP3cre(+) grafts. Collectively, these data indicate that autophagy-dependent Tregs are critical for the maintenance of tolerance after SCT and that the promotion of autophagy represents an attractive immune-restorative therapeutic strategy after allogeneic SCT.

Original languageEnglish
Pages (from-to)e86850
JournalJCI Insight
Volume1
Issue number15
DOIs
Publication statusPublished - 22 Sep 2016
Externally publishedYes

Keywords

  • Journal Article

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