Epithelial γδ T cell‐specific costimulation mediated by JAML‐CAR interactions

Abstract

γδ T cells in murine skin (DETC) represent a prototypical γδ intraepithelial lymphocyte population. They express an invariant γδ T cell receptor, Vγ3Vδ1, and play important roles as effectors and regulators of homeostasis through recognition of antigen expressed on damaged or diseased keratinocytes. DETC do not express many coreceptors important for αβ T cell activation. To date, no γδ‐specific accessory molecules have been described. Our recent focus has been to identify molecules on γδ T cells that play a key role in their activation and function. We have identified the first γδ T cell‐specific costimulatory molecule, Junctional Adhesion Molecule‐Like protein (JAML) and identify Coxsackie and Adenovirus Receptor (CAR) as its ligand. Only costimulation of epithelial γδ T cells occurs through JAML, αβ‐and lymphoid γδ T cells are unresponsive. JAML costimulation leads to cell proliferation and cytokine production through activation of MAP kinase pathways. Our results demonstrate a novel receptor‐ligand pair specific for epithelial γδ T cell function. In addition, the crystal structure of JAML reveals a unique Ig domain prototype that undergoes conformational changes upon ligand binding, suggesting a mechanism for initiating signaling through JAML. Experiments are underway to establish the role of JAML‐CAR interactions in epithelial γδ T cell responses during wound repair and other epithelial challenges.This work was supported by NIH grants AI32751 and AI52257 (W.L.H.), AI042266 and CA58896 (I.A.W.), an Erwin‐Schrödinger Fellowship of the Austrian Science Fund (P.V.) and The Leukemia and Lymphoma Society (S.E.R.).