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 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.