TY - JOUR
T1 - Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease
AU - Le Texier, Laëtitia
AU - Lineburg, Katie E.
AU - Cao, Benjamin
AU - McDonald-Hyman, Cameron
AU - Mouttie, Lucie Leveque El
AU - Nicholls, Jemma
AU - Melino, Michelle
AU - Nalkurthi, Blessy C.
AU - Alexander, Kylie A.
AU - Teal, Bianca
AU - Blake, Stephen J.
AU - Souza-Fonseca-Guimaraes, Fernando
AU - Engwerda, Christian R.
AU - Kuns, Rachel D.
AU - Lane, Steven W.
AU - Teng, Michele
AU - Teh, Charis
AU - Gray, Daniel
AU - Clouston, Andrew D.
AU - Nilsson, Susan K.
AU - Blazar, Bruce R.
AU - Hill, Geoffrey R.
AU - MacDonald, Kelli P.A.
N1 - Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/9/22
Y1 - 2016/9/22
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85055608990
UR - https://www.scopus.com/pages/publications/85055608990#tab=citedBy
U2 - 10.1172/jci.insight.86850
DO - 10.1172/jci.insight.86850
M3 - Article
C2 - 27699243
AN - SCOPUS:85055608990
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 15
M1 - e86850
ER -