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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autophagy / immunology
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Autophagy-Related Proteins
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B7-1 Antigen / biosynthesis
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B7-2 Antigen / biosynthesis
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CD4-Positive T-Lymphocytes / immunology*
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CD40 Antigens / biosynthesis
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CD8-Positive T-Lymphocytes / immunology*
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Carrier Proteins / genetics
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Carrier Proteins / immunology*
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Cell Proliferation
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Cells, Cultured
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Colitis / immunology
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Cysteine Endopeptidases / biosynthesis
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Dendritic Cells / immunology*
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Disease Models, Animal
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Female
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Graft vs Host Disease / immunology*
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Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
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Hematopoietic Stem Cell Transplantation
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Homeodomain Proteins / genetics
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Immediate-Early Proteins / biosynthesis
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Inflammation / immunology
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Intracellular Signaling Peptides and Proteins / biosynthesis
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Lymphocyte Activation / immunology
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Lysosomes / pathology
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Membrane Proteins / biosynthesis
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Receptors, Antigen, T-Cell, gamma-delta / immunology
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Transplantation, Homologous
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Tumor Necrosis Factor alpha-Induced Protein 3
Substances
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Atg16l1 protein, mouse
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Autophagy-Related Proteins
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B7-1 Antigen
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B7-2 Antigen
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CD40 Antigens
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Carrier Proteins
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Cd86 protein, mouse
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Homeodomain Proteins
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Immediate-Early Proteins
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Intracellular Signaling Peptides and Proteins
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Laptm5 protein, mouse
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Membrane Proteins
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Receptors, Antigen, T-Cell, gamma-delta
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RAG-1 protein
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Granulocyte-Macrophage Colony-Stimulating Factor
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Tumor Necrosis Factor alpha-Induced Protein 3
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Cysteine Endopeptidases
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Tnfaip3 protein, mouse
Associated data
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GEO/GSE61559
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GEO/GSE61560