The Purinergic G Protein-Coupled Receptor 6 Inhibits Effector T Cell Activation in Allergic Pulmonary Inflammation

We show that the P2Y6 receptor, a purinergic G protein-coupled receptor with a high affinity for the nucleotide uridine diphosphate, is an important endogenous inhibitor of T cell function in allergic pulmonary inflammation. Mice conditionally deficient in P2Y6 receptors [p2ry6 (flox/flox);cre/+ mice] exhibited severe airway and tissue pathology relative to P2Y6-sufficient [p2ry6 (flox/flox)] littermates (+/+ mice) when treated intranasally with an extract of the dust mite Dermatophagoides farinae (Df). P2Y6 receptors were inducibly expressed by lung, lymph node, and splenic CD4+ and CD8+ T cells of Df-treated +/+ mice. Df-restimulated P2Y6-deficient lymph node cells produced higher levels of Th1 and Th2 cytokines, and polyclonally stimulated P2Y6-deficient CD4+ T cells proliferated faster than comparably stimulated P2Y6-sufficient cells. The absence of P2Y6 receptors on CD4+ cells, but not APCs, was sufficient to amplify cytokine generation. Thus, P2Y6 receptors protect the lung against exuberant allergen-induced pulmonary inflammation by inhibiting the activation of effector T cells.