Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease
Laëtitia Le Texier, … , Geoffrey R. Hill, Kelli P.A. MacDonald
Laëtitia Le Texier, … , Geoffrey R. Hill, Kelli P.A. MacDonald
Published September 22, 2016
Citation Information: JCI Insight. 2016;1(15):e86850. https://doi.org/10.1172/jci.insight.86850.
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Research Article Immunology Transplantation

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

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. Nilsson, Bruce R. Blazar, Geoffrey R. Hill, Kelli P.A. MacDonald

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Figure 6

Autophagy-dependent BM Tregs are required to control GVHD after G-CSF–mobilized SCT.

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Autophagy-dependent BM Tregs are required to control GVHD after G-CSF–mo...
(A–D) Irradiated syngeneic Ptprca mice (CD45.1+, H2Db) or allogeneic B6D2F1 (CD45.2+, H2Db/d) recipients were transplanted with G-CSF–mobilized splenic graft from Atg7fl/fl-FoxP3cre+ (CD45.2+, H2Db) (Atg7–/–) or WT-FoxP3cre+ (CD45.2+, H2Db) (WT) mice (n = 5). (A) Outline of SCT strategy. (B) Survival curve (%) of allogeneic and syngeneic recipients after transplantation. Statistical significance was determined using log-rank (Mantel-Cox) test (****P < 0.001). (C) Pathology score from histopathology analysis of small intestine, colon, liver, and skin of allogeneic recipients and representative images of H&E staining of colon samples (n = 4 from 1 experiment). Original magnification, ×200. (D) Absolute number (#) of FoxP3neg CD8+ and CD4+ Tcon cells and CD4+Foxp3+ (Tregs) and TIGIT+ and TIGITneg Tregs from spleen of recipients (representative of 2 independent experiments with n = 4 in each experiments) and BM (n = 8 from 2 independent experiments) of allogeneic recipient mice 42 days after transplant. Data are shown as mean ± SEM. Statistical significance was determined using an unpaired 2-tailed Mann-Whitney U test (*P < 0.05). Statistical analyses were performed using GraphPad Prism version 6.01 software. GVHD, graft versus host disease; G-CSF, granulocyte-colony stimulating factor; SCT, stem cell transplantation; Atg, autophagy-related gene; SP, spleen; TIGIT, T cell immunoreceptor with Ig and ITIM domains.