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

Abstract

SUMMARY 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 co-stimulatory 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.

Acute graft-versus-host disease is more prevalent and severe in the lower than the upper gastrointestinal tract

“…Compared with the UGI tract, the colon hosts most anaerobic microorganisms at very high density (10 2 -10 3 versus 10 11 -10 12 bacteria/gram luminal contents) [29,30]. The role of microbiome in GI GVHD has been shown in several animal studies [31][32][33][34].…”

Role of Autophagy in the Maintenance of Intestinal Homeostasis

“…50 In a mouse model of graft versus host disease, deletion of Atg16l1 resulted in global dendritic cell activation, leading to increased T cell stimulation. 51 On the other hand, dendritic cells lacking Atg5 were unable to induce the differentiation of cytokine-producing CD4 + T cells during T. gondii infection. 52 Furthermore, dendritic cells from CD patients carrying risk variants in NOD2 and ATG16L1 showed defects in autophagy induction and MHC-II antigen presentation.…”

“…Autophagy plays an important role in several T cell-specific functions, including development, polarization, and memory. 51, 54-58 …”

Immune and myodegenerative pathomechanisms in inclusion body myositis

“…Intracellular antigen presentation via MHC class I molecules is also regulated by the autophagy machinery, because autophagy‐related proteins enhance MHC class I internalization for degradation and thereby diminish antigen display on the cell surface 268. Indeed, in vivo studies have primarily found enhanced CD8 + T cell responses in mice with defective autophagy in antigen‐presenting cells268, 269, 270 A potential mechanism leading to such increased CD8 + T cell expansions is that, in the absence of autophagy, more substrate becomes available for canonical MHC class I loading271 or by decreased endocytosis and degradation of cell surface MHC class I molecules 268. Thus, defective autophagy in skeletal muscle fibers could drive increased MHC class I expression and CD8 + T cell accumulation.…”