Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease
- Le Texier, L; Lineburg, KE; Cao, B; McDonald-Hyman, C; Leveque-El Mouttie, L; Nicholls, J; Melino, M; Nalkurthi, BC; Alexander, KA; Teal, B; Blake, SJ; Souza-Fonseca-Guimaraes, F; Engwerda, CR; Kuns, RD; Lane, SW; Teng, M; Teh, C; Gray, D; Clouston, AD; Nilsson, SK; Blazar, BR; Hill, GR; MacDonald, KP;
Publication Year 2016-09-22, Volume 1, Issue #15, Page e86850
- Journal Title
- JCI Insight
- Publication Type
- Journal Article
- 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.Atg7fl/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.Atg7fl/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.
- WEHI Research Division(s)
- Molecular Genetics Of Cancer
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Creation Date: 2016-10-19 11:52:30Last Modified: 2016-10-19 12:14:58