title: Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells.
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.
authors.affiliation: 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.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hubbard-Lucey
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Shono
authors.affiliation: 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.
authors.forename: Katie
authors.initials: K
authors.lastname: Maurer
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mallory L
authors.initials: ML
authors.lastname: West
authors.affiliation: Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Natalie V
authors.initials: NV
authors.lastname: Singer
authors.affiliation: Department of Computational Biology and Immunology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Carly G K
authors.initials: CG
authors.lastname: Ziegler
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Lezcano
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ana Carolina Fragoso
authors.initials: AC
authors.lastname: Motta
authors.affiliation: Department of Haematology and Oncology, University Medical Centre University of Regensburg, Regensburg, 93053, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schmid
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA.
authors.forename: Samuel M
authors.initials: SM
authors.lastname: Levi
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32611, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Chemistry, University of Pennsylvania, Philadelphia, PA, 19104, USA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Winkler
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.affiliation: Department of Gastroenterology, University Hospital Zürich, Rämistrasse 100, 8006 Zurich, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.affiliation: Haematological Sciences, Institute of Cellular Medicine, Newcastle University, NE2 4HH Tyne and Wear, UK.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Dickinson
authors.affiliation: Department of Haematology and Oncology, University Medical Centre University of Regensburg, Regensburg, 93053, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Holler
authors.affiliation: 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.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: 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.
authors.forename: Ken
authors.initials: K
authors.lastname: Cadwell
mesh_terms: D000818:Animals; D001343:Autophagy / Q000276:immunology; D000071183:Autophagy-Related Proteins; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D003092:Colitis / Q000276:immunology; D003546:Cysteine Endopeptidases / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D018380:Hematopoietic Stem Cell Transplantation; D018398:Homeodomain Proteins / Q000235:genetics; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D008247:Lysosomes / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D014184:Transplantation, Homologous; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: C532820:Atg16l1 protein, mouse; D000071183:Autophagy-Related Proteins; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D002352:Carrier Proteins; C497965:Cd86 protein, mouse; D018398:Homeodomain Proteins; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; C484408:Laptm5 protein, mouse; D008565:Membrane Proteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; C064658:RAG-1 protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse