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 2

Treg-intrinsic autophagy deficiency results in immune pathology in aged mice.

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Treg-intrinsic autophagy deficiency results in immune pathology in aged ...
(A and B) Flow cytometry analysis of WT-FoxP3cre+ (WT) and Atg7fl/fl-FoxP3cre+ (Atg7–/–) mice (n = 4 from 2 independent experiments). (A) Representative dot plot of MCL-1 and FoxP3+ expression in CD4+CD8–CD3+ splenic T cells. Representative histogram and geometric mean of MCL-1 expression in FoxP3+CD4+CD8–CD3+ splenic T cells. (B) Representative histogram and frequency (%) of Ki67+ expression in FoxP3+ CD4+CD8–CD3+ splenic T cells. (C) Histopathology analysis of Atg7fl/fl-FoxP3cre+ (Atg7–/–) mice compared with WT-FoxP3cre+ (WT) mice. Representative pictures of aged mice (32–44 weeks). Representative images of H&E and Masson’s trichrome staining of skin samples. Representative images of H&E staining and pathology score of skin, small intestine (SI), and liver samples (n = 4, WT; n = 7–8, Atg7–/–). Original magnification, ×200. Body weight of mice (30–37 weeks) (n = 4–6). Data are shown as mean ± SEM. Statistical significance was determined using an unpaired 2-tailed Mann-Whitney U test (*P < 0.05, **P < 0.01). Statistical analyses were performed using GraphPad Prism version 6.01 software. Atg, autophagy-related gene; MCL-1, myeloid cell leukemia 1.