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

•Mice deficient in autophagy gene Atg16l1 are susceptible to graft-versus-host disease•Autophagy-deficient dendritic cells become hyperactive following an HSC transplant•Hyperactive dendritic cells stimulate donor T cells that damage the intestine

SummaryAtg16L1 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.

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