Enteric Glia Regulate Lymphocyte Activation via Autophagy-Mediated MHC-II Expression

BACKGROUND & AIMS: Enteric glial cells express type II major histocompatibility complex (MHC-II) molecules in Crohn’s disease and Chagas disease, but it is unclear whether the expressed molecules are functional. We examined the capabilities of enteric glia to act as an antigen-presenting cell in vivo and whether glial MHC-II has immunomodulatory effects. METHODS: We generated Sox10(CreERT2);IAB(fl/fl) mice to ablate MHC-II in enteric glia after exposure to tamoxifen. We measured phagocytic activity and autophagy activation to assess potential peptide sources loaded onto glial MHC-II and measured T- and B-lymphocyte activation and serum and colonic tissue cytokine levels to study enteric glial immunomodulatory capabilities. RESULTS: Enteric glia express MHC-II molecules in response to a subclinical dose of interferon-γ and lipopolysaccharide in vivo. Glial MHC-II expression contributes to effective B-lymphocyte and T-lymphocyte activation with marked effects on T-helper cell (Th)17 and regulatory T cell subtypes. No effect on Th1 or Th2 subtypes was observed. Enteric glial MHC-II does not have a major effect on serum or colonic tissue cytokine levels but may influence local cytokine levels. Glial MHC-II expression requires the activation of autophagy pathways, but activating autophagy alone is not sufficient to drive glial MHC-II expression. CONCLUSIONS: Enteric glia express MHC-II as a mechanism to tune intestinal immune responses. Glial autophagy is triggered in response to proinflammatory stimuli and induces glial antigen presentation, which functions to modulate the activation of T-lymphocyte subsets involved in tolerance. These observations suggest that enteric glia may express MHC-II to maintain immune homeostasis during inflammatory conditions such as Crohn’s disease.