IL-27 Receptor Signaling Regulates CD4+ T Cell Chemotactic Responses during Infection

IL-27 exerts pleiotropic suppressive effects on naive and effector T cell populations during infection and inflammation. Surprisingly, however, the role of IL-27 in restricting or shaping effector CD4+ T cell chemotactic responses, as a mechanism to reduce T cell–dependent tissue inflammation, is unknown. In this study, using Plasmodium berghei NK65 as a model of a systemic, proinflammatory infection, we demonstrate that IL-27R signaling represses chemotaxis of infection-derived splenic CD4+ T cells in response to the CCR5 ligands, CCL4 and CCL5. Consistent with these observations, CCR5 was expressed on significantly higher frequencies of splenic CD4+ T cells from malaria-infected, IL-27R–deficient (WSX-1−/−) mice than from infected wild-type mice. We find that IL-27 signaling suppresses splenic CD4+ T cell CCR5-dependent chemotactic responses during infection by restricting CCR5 expression on CD4+ T cell subtypes, including Th1 cells, and also by controlling the overall composition of the CD4+ T cell compartment. Diminution of the Th1 response in infected WSX-1−/− mice in vivo by neutralization of IL-12p40 attenuated CCR5 expression by infection-derived CD4+ T cells and also reduced splenic CD4+ T cell chemotaxis toward CCL4 and CCL5. These data reveal a previously unappreciated role for IL-27 in modulating CD4+ T cell chemotactic pathways during infection, which is related to its capacity to repress Th1 effector cell development. Thus, IL-27 appears to be a key cytokine that limits the CCR5-CCL4/CCL5 axis during inflammatory settings.