The Role of CC chemokine Receptors 6 and 7 in the Immune Response to Respiratory Syncytial Virus.

Abstract

Chemokines and chemokine receptors promote the migration of immune cells during infectious stimuli as well as under homeostatic conditions. In chronic disease, chemokines can also promote influx of cells that contributes to pathological inflammation. Respiratory syncytial virus (RSV) is a negative sense RNA virus that is the primary cause of hospitalization in children under the age of 2. Pathologic immune responses are thought to be responsible for RSV-associated disease. This study investigated the role of two chemokine receptors, CC chemokine receptors 6 and 7 (CCR6 and CCR7), expressed by leukocytes, in the immune response to RSV infection. Animals deficient in CCR6 and infected with RSV had enhanced viral clearance, diminished mucus production, and generated a protective Th1 effector T cell response in comparison to wild-type mice. The tempered pathological response in CCR6-/- animals was due to the impaired recruitment of dendritic cells (DC) in the lung, which promoted Th2 cytokines and mucus production when adoptively transferred into CCR6-/- mice. Conversely, CCR7-/-animals infected with RSV exhibited an exacerbated, dysregulated effector T cell response in the lung as a result of impaired migration of cells to the lymph nodes and thus local priming of the immune response. Restoration of immune cell trafficking to the lymph nodes in bone marrow chimeras reestablished effector T cell responses and abrogated local pathology. These studies demonstrate important roles for chemokine receptor-mediated immune cell trafficking in contributing to tissue pathology as well as modulating responses to RSV infection.