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Autophagy Gene Atg16l1 Prevents Lethal T Cell Alloreactivity Mediated by Dendritic Cells

Lookup NU author(s): Professor Anne Dickinson

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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 metadata

Author(s): Hubbard-Lucey VM, Shono Y, Maurer K, West ML, Singer NV, Ziegler CGK, Lezcano C, Motta ACF, Schmid K, Levi SM, Murphy GF, Liu C, Winkler JD, Amaravadi RK, Rogler G, Dickinson AM, Holler E, van den Brink MRM, Cadwell K

Publication type: Article

Publication status: Published

Journal: Immunity

Year: 2014

Volume: 41

Issue: 4

Pages: 579-591

Print publication date: 16/10/2014

Online publication date: 09/10/2014

Acceptance date: 13/09/2014

ISSN (print): 1074-7613

ISSN (electronic): 1097-4180

Publisher: Cell Press

URL: http://dx.doi.org/10.1016/j.immuni.2014.09.011

DOI: 10.1016/j.immuni.2014.09.011

PubMed id: 25308334


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Funding

Funder referenceFunder name
Dale F. Frey Award from the Damon Runyon Cancer Research Foundation
Susan and Peter Solomon Divisional Genomics Program
Lymphoma Foundation
Lymphoma Research Foundation Post-Doctoral Fellowship Research Grant
Uehara Memorial Foundation
3347CO-108792Swiss IBD Cohort Study
602587European Union's Seventh Programme
AI100288US National Institute of Health (NIH)
F30 DK098925US National Institute of Health (NIH)
F32 HL115974US National Institute of Health (NIH)
HHSN272200900059CU.S. National Institute of Allergy and Infectious Diseases (NIAID)
P01 CA023766US National Institute of Health (NIH)
R01 HL069929US National Institute of Health (NIH)
P01-CA023766US National Institute of Health (NIH)
T32 AI007647US National Institute of Health (NIH)
T32 AI100853US National Institute of Health (NIH)
R01 AI080455US National Institute of Health (NIH)
R01 AI101406US National Institute of Health (NIH)
R01 DK093668US National Institute of Health (NIH)
T32 GM0738US National Institute of Health (NIH)

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