title: Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease.
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.
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Le Texier
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Katie E
authors.initials: KE
authors.lastname: Lineburg
authors.affiliation: Manufacturing, Commonwealth Scientific and Industrial Research Organization (CSIRO), Melbourne, Victoria, Australia.|Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Cao
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: McDonald-Hyman
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Lucie
authors.initials: L
authors.lastname: Leveque-El Mouttie
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Jemma
authors.initials: J
authors.lastname: Nicholls
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Michelle
authors.initials: M
authors.lastname: Melino
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Blessy C
authors.initials: BC
authors.lastname: Nalkurthi
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: Alexander
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Bianca
authors.initials: B
authors.lastname: Teal
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Blake
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Fernando
authors.initials: F
authors.lastname: Souza-Fonseca-Guimaraes
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Engwerda
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Kuns
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|Department of Bone Marrow Transplantation, Royal Brisbane Hospital, Brisbane, Queensland, Australia.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Lane
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Michele
authors.initials: M
authors.lastname: Teng
authors.affiliation: Molecular Genetics of Cancer Division and Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Charis
authors.initials: C
authors.lastname: Teh
authors.affiliation: Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.|Molecular Genetics of Cancer Division and Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Gray
authors.affiliation: Envoi Specialist Pathologists, Brisbane, Queensland, Australia.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.affiliation: Manufacturing, Commonwealth Scientific and Industrial Research Organization (CSIRO), Melbourne, Victoria, Australia.|Australian Regenerative Medicine Institute, Monash University, Melbourne, Victoria, Australia.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Nilsson
authors.affiliation: Pediatric Blood and Marrow Transplantation Program, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.|Department of Bone Marrow Transplantation, Royal Brisbane Hospital, Brisbane, Queensland, Australia.
authors.forename: Geoffrey R
authors.initials: GR
authors.lastname: Hill
authors.affiliation: Immunology Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
authors.forename: Kelli Pa
authors.initials: KP
authors.lastname: MacDonald
mesh_terms: D000818:Animals; D001343:Autophagy; D001853:Bone Marrow / Q000503:physiopathology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*