Autophagy-dependent regulatory T cells are critical for the control of graft-versus-host disease
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
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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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 7

Autophagy-dependent BM Tregs are required to control GVHD and survival after BMT.

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Autophagy-dependent BM Tregs are required to control GVHD and survival a...
(A–E) Irradiated allogeneic B6D2F1 (CD45.2+, H2Db/d) recipient mice were transplanted with BM graft alone (T cell–depleted [TCD] BM) or BM + T cell graft (BM + T) composed of sorted Tregs (YFP+) + Tcon (YFPneg) cells from either Atg7fl/fl-FoxP3cre+ (Atg7–/–) or WT-FoxP3cre+ mice (WT). Analysis at day 28 after transplantation (BM + T) or day 28 to 41 (BM TCD). (A) Outline of SCT strategy. (B) GVHD clinical scores of recipients after transplantation (****P < 0.0001) (n = 6–16 from 2 independent experiments). (C) Survival curve (%) of recipient mice after transplantation. Statistical significance was determined using log-rank (Mantel-Cox) test (*P < 0.05) (n = 6 from 1 experiment). (D) IFN-γ quantification in sera (**P < 0.01) (n = 8–10 from 2 independent experiments). (E) Absolute number (#) of CD8+CD3+ Tcon cells (CD8), FoxP3neg CD4+CD3+ Tcon cells (CD4), CD4+Foxp3+ Tregs (Tregs), and TIGIT+ and TIGITneg Tregs from spleen and BM (n = 8–10 from 2 independent experiments) of recipient mice in the BM + T setting. Data are shown as mean ± SEM. Statistical significance was determined using an unpaired 2-tailed Mann-Whitney U test (*P < 0.05; ***P < 0.001). Statistical analyses were performed using GraphPad Prism version 6.01 software. GVHD, graft versus host disease; BMT, bone marrow transplantation; YFP, yellow fluorescent protein; Tcon, conventional T cells; Atg,autophagy-related gene; TCD, T cell depleted; TIGIT, T cell immunoreceptor with Ig and ITIM domains.