Sjogren's syndrome is an autoimmune disease characterized by lymphocytic infiltration of the salivary glands. In the NOD mouse, a model for this disease, the development of lymphocytic infiltrates in the salivary glands is preceded by an accumulation of dendritic cells ( DC). Given the key importance of DC in regulating the immune response, we characterized the DC isolated from NOD salivary glands. These DC lacked membrane expression of CCR5, whereas DC from control salivary glands did express this molecule. The lack of expression was present already prior to the onset of lymphocytic infiltration, indicating that this was not the result of ongoing inflammation. DC from other sources in the NOD mouse also showed a decrease in CCR5 expression. The lack of CCR5 expression in the NOD salivary gland was accompanied by an increase in inflammatory chemokines. Furthermore, DC from CCR5-/- animals or DC treated with a CCR5 antagonist showed increased secretion of IL-12. Interestingly, in Sjogren's syndrome patients, CCR5 expression on circulating monocytes was decreased and correlated to increased levels of IL-12. These data indicate that CCR5 has regulatory properties and that the lack of CCR5 in NOD DC contributes to the proinflammatory environment in the salivary glands.