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

Texier, Laëtitia Le; Lineburg, Katie E.; Cao, Benjamin; McDonald-Hyman, Cameron; Mouttie, Lucie Leveque-El; Nicholls, Jemma; Melino, Michelle; Nalkurthi, B Christina; Alexander, Kylie A.; Teal, Bianca E.; Blake, Stephen J.; Souza-Fonseca-Guimarães, Fernando; Engwerda, Christian; Kuns, Rachel D.; Lane, Steven; Teng, Michele W.L.; Teh, Charis E.; Gray, Daniel H.D.; Clouston, Andrew D.; Nilsson, Susan K.; Blazar, Bruce R.; Hill, Geoffrey R.; MacDonald, Kelli P. A.

doi:10.1172/jci.insight.86850

Cited by 49 publications

(60 citation statements)

References 65 publications

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“…Autophagy-related protein 16-1 (ATG16L1) contributes a critical role in autophagy and ATG16L1 dysfunction leads to immune diseases such as Crohn’s Disease and decreased antibacterial defense 11 , 12 . Since autophagy-dependent tTreg cells are critical for the control of GVHD 13 , we hypothesized that targeting ATG may improve tTreg survival.…”

Section: Introductionmentioning

confidence: 99%

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

Gao

Zhang

et al. 2018

Cell Death Dis

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Thymic-derived regulatory T cell (tTreg) clinical trials show therapeutic promise in the prevention of acute graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation patients. However, strategies are needed to improve tTreg proliferative ability and survival as a means to improve tTreg therapy and reduce the requirement for producing large numbers of Treg cells for adoptive tTreg transfer. Autophagy is a self-degradative process for cytosolic components, which is involved in cells death, differentiation, lymphocyte homeostasis, and tTreg function. Studies have shown that mice with tTreg cells that have a disrupted autophagy process have defective tTreg cell generation and function, resulting in autoimmune disease and failed GVHD prevention by adoptively transferred tTreg cells. We found the attenuated autophagy status during ex vivo expansion, which leads us to determine whether tTreg cell survival could be augmented by miR-142-3p, the miRNA which is highly expressed in tTreg cells and potentially targets autophagy-related protein (ATG)-1, ATG16L1. We demonstrate that miR-142-3p downregulates ATG16L1 mRNA and production of ATG16L1, that has been linked to autoimmune diseases. Conversely, miR-142-3p knock-down improved tTreg cell expansion, survival and function in vitro and vivo. In aggregate, these studies provide a new approach that uses miR-142-3p knockdown to increase tTreg cell efficacy by increasing ATG16L1 mRNA and protein and the autophagy process.

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Section: Introductionmentioning

confidence: 99%

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

Gao

Zhang

et al. 2018

Cell Death Dis

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“…There is also a growing focus in the field in identifying cellular biomarkers of this disease. This work has been driven by detailed flow cytometric evaluation of the T-and B-cell subpopulations driving both acute and chronic disease, [86][87][88][89][90][91][92][93][94][95][96][97][98][99][100][101][102] as well as increasing use of systems-based transcriptomic approaches to identifying the pathways associated with GVHD, both in preclinical models and clinical samples. 50, [103][104][105][106][107] This work is identifying a new cohort of targetable pathways for GVHD control, many of which are amenable for clinical translation.…”

Section: Postneutrophil Engraftmentmentioning

confidence: 99%

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

Kean

2018

Blood

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Cellular therapies play a major and expanding role in the treatment of hematologic diseases. For each of these therapies, a narrow therapeutic window exists, where efficacy is maximized and toxicities minimized. This review focuses on one of the most established cellular therapies, hematopoietic stem cell transplant, and one of the newest cellular therapies, chimeric antigen receptor-T cells. In this review, I will discuss the current state of the field for clinical end point analysis with each of these therapeutics, including their critical toxicities, and focus on the major elements of success for each of these complex treatments for hematologic disease.

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“…Within the hematopoietic system, autophagy has diverse roles and is required for hematopoietic stem cell (HSC) function 2 , differentiation into erythroid 3 or T-lymphoid lineages 4,5 and response to extracellular cytokine signaling 6 . In blood cancers such as acute myeloid leukaemia (AML), modulating autophagy has been proposed as a novel therapy to treat AML 1,7,8 .…”

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confidence: 99%

“…Similarly, loss of other critical regulators such as Atg5 result in impaired autophagic flux. Autophagy regulates several important processes in the hematopoietic system including HSC maintenance, cytokine responsiveness and T-cell homeostasis 2,3,5,6 .…”

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confidence: 99%

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Acute myeloid leukemia stem cell function is preserved in the absence of autophagy

et al. 2017

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

Cited by 49 publications

References 65 publications

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

miR-142-3p regulates autophagy by targeting ATG16L1 in thymic-derived regulatory T cell (tTreg)

Defining success with cellular therapeutics: the current landscape for clinical end point and toxicity analysis

Acute myeloid leukemia stem cell function is preserved in the absence of autophagy

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