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Immunity. 2014 Oct 16;41(4):579-91. doi: 10.1016/j.immuni.2014.09.011. Epub 2014 Oct 9.

Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells.

Author information

1
Kimmel Center for Biology and Medicine at the Skirball Institute, New York, NY 10016, USA; Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA.
2
Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
3
Kimmel Center for Biology and Medicine at the Skirball Institute, New York, NY 10016, USA; Sackler Institute of Graduate Biomedical Sciences, New York University School of Medicine, New York, NY 10016, USA.
4
Department of Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
6
Department of Haematology and Oncology, University Medical Centre University of Regensburg, Regensburg, 93053, Germany.
7
Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA.
8
Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32611, USA.
9
Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
10
Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
11
Department of Gastroenterology, University Hospital Zürich, Rämistrasse 100, 8006 Zurich, Switzerland.
12
Haematological Sciences, Institute of Cellular Medicine, Newcastle University, NE2 4HH Tyne and Wear, UK.
13
Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: vandenbm@mskcc.org.
14
Kimmel Center for Biology and Medicine at the Skirball Institute, New York, NY 10016, USA; Department of Microbiology, New York University School of Medicine, New York, NY 10016, USA. Electronic address: ken.cadwell@med.nyu.edu.

Abstract

Atg16L1 mediates the cellular degradative process of autophagy and is considered a critical regulator of inflammation based on its genetic association with inflammatory bowel disease. Here we find that Atg16L1 deficiency leads to an exacerbated graft-versus-host disease (GVHD) in a mouse model of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Atg16L1-deficient allo-HSCT recipients with GVHD displayed increased T cell proliferation due to increased dendritic cell (DC) numbers and costimulatory molecule expression. Reduced autophagy within DCs was associated with lysosomal abnormalities and decreased amounts of A20, a negative regulator of DC activation. These results broaden the function of Atg16L1 and the autophagy pathway to include a role in limiting a DC-mediated response during inflammatory disease, such as GVHD.

PMID:
25308334
PMCID:
PMC4237219
DOI:
10.1016/j.immuni.2014.09.011
[Indexed for MEDLINE]
Free PMC Article

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