Matsuzawa-Ishimoto et al. show that autophagy gene ATG16L1, which is associated with inflammatory diseases of the gastrointestinal tract, is essential for preventing necroptotic cell death and loss of Paneth cells in the intestinal epithelium.

The cellular degradative pathway of autophagy has a fundamental role in immunity. Here, we review the function of autophagy and autophagy proteins in inflammation. We discuss how the autophagy machinery controls the burden of infectious agents while simultaneously limiting inflammatory pathologies, which often involves processes that are distinct from conventional autophagy. Among the newly emerging processes we describe are LC3-associated phagocytosis and targeting by autophagy proteins, both of which require many of the same proteins that mediate conventional autophagy. We also discuss how autophagy contributes to differentiation of myeloid and lymphoid cell types, coordinates multicellular immunity, and facilitates memory responses. Together, these functions establish an intimate link between autophagy, mucosal immunity, and chronic inflammatory diseases. Finally, we offer our perspective on current challenges and barriers to translation.

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Products derived from bacterial members of the gut microbiota evoke immune signaling pathways from the host that promote immunity and barrier function in the intestine. How immune reactions to enteric viruses support intestinal homeostasis is unknown. Recently, we demonstrated that infection by murine norovirus (MNV) reverses intestinal abnormalities upon depletion of bacteria, indicating that an intestinal animal virus can provide cues to the host that are typically attributed to the microbiota. Here, we elucidate mechanisms by which MNV evokes protective responses from the host. We identify an important role for the viral protein NS1/2 in establishing local replication and a type I interferon (IFN-I) response in the colon. We further show that IFN-I acts on intestinal epithelial cells to increase the proportion of CCR2-dependent macrophages and IL-22 producing innate lymphoid cells (ILCs), which in turn promote pSTAT3 signaling in intestinal epithelial cells and protection from intestinal injury. Additionally, we demonstrate that MNV provides a striking IL-22 dependent protection against early life lethal infection by Citrobacter rodentium. These findings demonstrate novel ways in which a viral member of the microbiota fortifies the intestinal barrier during chemical injury and infectious challenges.

A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell–mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues.

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