Journal article
Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease
JCI Insight, Vol.1(15), e86850
2016
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.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.
Details
- Title
- Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease
- Authors
- L Le Texier (Author) - QIMR Berghofer Medical Research InstituteK E Lineburg (Author) - QIMR Berghofer Medical Research InstituteB Cao (Author) - Commonwealth Scientific and Industrial Research OrganisationC McDonald-Hyman (Author) - University of MinnesotaL Leveque-El Mouttie (Author) - QIMR Berghofer Medical Research InstituteJemma Nicholls (Author) - QIMR Berghofer Medical Research InstituteM Melino (Author) - QIMR Berghofer Medical Research InstituteB C Nalkurthi (Author) - QIMR Berghofer Medical Research InstituteK A Alexander (Author) - QIMR Berghofer Medical Research InstituteB Teal (Author) - QIMR Berghofer Medical Research InstituteStephen J Blake (Author) - QIMR Berghofer Medical Research InstituteFernando Souza-Fonseca-Guimaraes (Author) - QIMR Berghofer Medical Research InstituteChristian R Engwerda (Author) - QIMR Berghofer Medical Research InstituteRachel D Kuns (Author) - QIMR Berghofer Medical Research InstituteSteven W Lane (Author) - QIMR Berghofer Medical Research InstituteMichele Teng (Author) - QIMR Berghofer Medical Research InstituteCharis Teh (Author) - Walter and Eliza Hall Institute of Medical ResearchDaniel Gray (Author) - Walter and Eliza Hall Institute of Medical ResearchAndrew D Clouston (Author) - Envoi Specialist Pathologists (Australia)Susan K Nilsson (Author) - Commonwealth Scientific and Industrial Research OrganisationBruce R Blazar (Author) - University of MinnesotaGeoffrey R Hill (Author) - QIMR Berghofer Medical Research InstituteKelly P A MacDonald (Author) - QIMR Berghofer Medical Research Institute
- Publication details
- JCI Insight, Vol.1(15), e86850
- Publisher
- American Society for Clinical Investigation
- Date published
- 2016
- DOI
- 10.1172/jci.insight.86850
- ISSN
- 2379-3708
- Organisation Unit
- School of Health and Sport Sciences - Legacy
- Language
- English
- Record Identifier
- 99450865902621
- Output Type
- Journal article
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