The role of JAML-CAR costimulation in gamma delta T cell-mediated repair of the intestinal epithelium

Abstract

Abstract Tissue-resident γδ T cells are key players in the maintenance of the body’s epithelial barrier surfaces and perform an essential role in promoting tissue repair. Although γδ IELs are important coordinators of repair in the intestinal epithelium, relatively little is known about how these cells recognize and respond to damage. Recognition of skin wounds by γδ T cells requires costimulation through the junctional adhesion molecule-like protein (JAML) by ligation of coxsackie and adenovirus receptor (CAR), raising the possibility that these molecules may have a similar function in the gut. Here we evaluated the role of JAML-CAR costimulation in the activation and function of γδ IELs using the dextran sulfate sodium (DSS) model of intestinal injury and repair. Following DSS treatment we found that γδ IELs upregulated their surface expression of JAML and observed a shift in the isoforms of CAR expressed by intestinal epithelial cells. In addition, JAML−/− mice exhibited more severe weight loss and epithelial damage than wildtype animals in response to DSS treatment. While we saw that JAML−/− mice had lower numbers of IELs in the colon, this difference did not account for the more severe response to DSS-induced injury in these animals. Importantly, the activation of γδ IELs following DSS treatment was reduced in the absence of JAML-CAR costimulation. In addition, we found evidence of impaired γδ IEL production of IL-17, a cytokine known to protect against DSS-induced epithelial injury. Taken together our results suggest that JAML-CAR costimulation may be needed for the activation of tissue repair functions in γδ T cells across barrier tissues and supports targeting this pathway for therapeutic approaches for the acceleration of healing.