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 3

Autophagy is required to maintain the CD4+FoxP3+Helios+TIGIT+ Treg subset.

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Autophagy is required to maintain the CD4+FoxP3+Helios+TIGIT+ Treg subse...
(A–C) Cytometry analysis of Tregs from Atg7–/– and WT mixed chimera generated by injecting BM from Atg7fl/fl-FoxP3cre+ (CD45.2+) (Atg7–/–) or WT-FoxP3cre+ (CD45.2+) (WT) mice with an equal number of BM cells from congenic (CD45.1+CD45.2+) mice into irradiated syngeneic Ptprca mice (CD45.1+) (n = 5). (A) Outline of mixed chimera mouse transplant strategy. (B) Frequency (%) of Helios+ and Heliosneg and (C) frequency (%) and absolute number (#) of TIGIT+ and TIGITneg Tregs gated on FoxP3+CD4+CD8–CD3+CD45.2+ cells in spleen and BM. (D) Representative zebra plot of flow cytometry analysis and frequency (%) of Helios and TIGIT expression on FoxP3+CD4+CD8–CD3+ (Tregs), FoxP3negCD4+CD8–CD3+ (CD4 Tcon), and FoxP3negCD8+CD4–CD3+ (CD8 Tcon) cells analyzed in thymus, spleen, and BM of FoxP3-GFP mice (n = 4–8 from 2 independent experiments). 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; ***P < 0.001). Statistical analyses were performed using GraphPad Prism version 6.01 software. Atg, autophagy-related gene; TIGIT, T cell immunoreceptor with Ig and ITIM domains; Tcon, conventional T cells.