Epstein-Barr virus induces B cell migration and diapedesis

Infection with the Epstein-Barr virus (EBV) is a major risk factor for the development of cancer and autoimmune disorders. The virus enters the body in the pharynx, but EBV causes disease in distant organs, including the gut and the brain. Here we show that infected B cells display features of homing cells. First, they undergo migration through chemokinesis induced by paracrine CCL4 release and CCR1 activation, two molecules induced by the virus. CCR1 knockout inhibited migration and, unexpectedly, proliferation of infected B cells. Second, migrating EBV-infected cells disrupted the integrity of endothelial barriers and underwent diapedesis very efficiently. This process was again dependent on CCL4 and its ability to induce ICAM-1 on endothelial cells. Migration and diapedesis converged on the FAK kinase whose inhibition blocked cell growth and survival of EBV-transformed B cells, but also their spreading to spleen and brain in an animal model in vivo. Moreover, IL-10 secreted by EBV-infected B cells attracted and facilitated diapedesis of EBV-negative CD52high primary B cells. Among these, CD11c+ cells that have been implicated in the pathogenesis of autoimmune diseases were preferentially represented. Curbing migration offers an opportunity to reduce the pathogenicity of EBV-infected B cells in diseased individuals.