The Junctional Adhesion Molecule JAML Is a Costimulatory Receptor for Epithelial γδ T Cell Activation

Skin Reaction Lymphocytes in the skin known as γδ T cells provide an important barrier against infection and injury. Unlike classical αβ T cells, less is known about the molecular requirements of γδ T cell activation. Two studies demonstrate that the junctional adhesion molecule–like protein (JAML) is a costimulatory molecule for mouse γδ T. Witherden et al. (p. 1205; see the Perspective by Shaw and Huang) showed that JAML, binding to its ligand Coxsackie and adenovirus receptor (CAR), leads to proliferation, as well as cytokine and growth factor production by γδ T cells. In vivo, JAML-CAR interactions contributed to the wound healing response in mice. Verdino et al. (p. 1210; see the Perspective by Shaw and Huang) present a crystal structure of CAR/JAML, which revealed an intracellular signaling motif similar to that known for the αβ T cell costimulatory receptor that signals through phosphoinositide 3-kinase. A costimulatory receptor for immune cells in the skin is identified. γδ T cells present in epithelial tissues provide a crucial first line of defense against environmental insults, including infection, trauma, and malignancy, yet the molecular events surrounding their activation remain poorly defined. Here we identify an epithelial γδ T cell–specific costimulatory molecule, junctional adhesion molecule–like protein (JAML). Binding of JAML to its ligand Coxsackie and adenovirus receptor (CAR) provides costimulation leading to cellular proliferation and cytokine and growth factor production. Inhibition of JAML costimulation leads to diminished γδ T cell activation and delayed wound closure akin to that seen in the absence of γδ T cells. Our results identify JAML as a crucial component of epithelial γδ T cell biology and have broader implications for CAR and JAML in tissue homeostasis and repair.