The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation

Abstract

A polymorphism in the autophagy gene Atg16l1 is associated with susceptibility to inflammatory bowel disease (IBD); however, it remains unclear how autophagy contributes to intestinal immune homeostasis. Here, we demonstrate that autophagy is essential for maintenance of balanced CD4+ T cell responses in the intestine. Selective deletion of Atg16l1 in T cells in mice resulted in spontaneous intestinal inflammation that was characterized by aberrant type 2 responses to dietary and microbiota antigens, and by a loss of Foxp3+ Treg cells. Specific ablation of Atg16l1 in Foxp3+ Treg cells in mice demonstrated that autophagy directly promotes their survival and metabolic adaptation in the intestine. Moreover, we also identify an unexpected role for autophagy in directly limiting mucosal TH2 cell expansion. These findings provide new insights into the reciprocal control of distinct intestinal TH cell responses by autophagy, with important implications for understanding and treatment of chronic inflammatory disorders.DOI: http://dx.doi.org/10.7554/eLife.12444.001

Ancient Nuclear Receptor VDR With New Functions: Microbiome and Inflammation

“…Targeted deletion of ATG16L1 in CD4+ T cells results in increased Th2 expansion and impaired Treg development leading to spontaneous intestinal inflammation. 49 Overall, induction of Atg16l1 expression by VDR 13 in intestinal epithelial cells may play a critical role in maintaining intestinal homeostasis.…”

Mechanistic roles of autophagy in hematopoietic differentiation

“…Similar to T MEM , regulatory T cells (T reg ) are antigen-experienced cells that maintain a state of readiness over an extended period of time that allows them to respond quickly if and when they are needed. While in this homeostatic, nonproliferative state, T reg cells switch to FAO-driven OXPHOS as main fuel source and have elevated levels of autophagy [50][51][52]. Two recent studies have shown that autophagy is indeed an essential player in T reg -cell maintenance and function by supporting their metabolic adaption and prevention of excessive glycolysis [51,53].…”

“…While in this homeostatic, nonproliferative state, T reg cells switch to FAO-driven OXPHOS as main fuel source and have elevated levels of autophagy [50][51][52]. Two recent studies have shown that autophagy is indeed an essential player in T reg -cell maintenance and function by supporting their metabolic adaption and prevention of excessive glycolysis [51,53]. While the authors note a decrease in the terminal differentiation marker KLRG-1 in T reg cells from Atg16l1 f/f 9 foxp3-Cre mice, they conclude that autophagy deficiency mainly affects T reg -cell maintenance and survival in the context of metabolic adaptation to the intestinal microenvironment.…”

Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease

“…S5). Further, recent reports reveal a role for autophagy components in T reg homeostasis (34, 35). Our findings indicate that ATG16L1-deficient DCs fail to respond to B. fragilis OMVs, demonstrating that autophagy components in DCs are required for commensal-driven T reg induction and function.…”