Differential response of BDCA-1+ and BDCA-3+ myeloid dendritic cells to respiratory syncytial virus infection.

backgroundRespiratory syncytial virus (RSV) is the leading cause of respiratory infections in children, elderly, and immunocompromised individuals. Severe infection is associated with short- and long-term morbidity including pneumonia, recurrent wheezing, and abnormal pulmonary function, and several lines of evidence indicate that impaired adaptive immune responses during infection are critical in the pathophysiology of RSV-mediated disease. Myeloid Dendritic cells (mDCs) play a pivotal role in shaping antiviral immune responses in the respiratory tract; however, few studies have examined the interactions between RSV and individual mDC subsets. In this study, we examined the effect of RSV on the functional response of primary mDC subsets (BDCA-1(+) and BDCA-3(+)) isolated from peripheral blood.

methodsBDCA-1(+) and BDCA-3(+) mDCs were isolated from the peripheral blood of healthy adults using FACS sorting. Donor-matched BDCA-1(+) and BDCA-3(+) mDCs were infected with RSV at a multiplicity of infection (MOI) of 5 for 40 hours. After infection, cells were analyzed for the expression of costimulatory molecules (CD86, CD80, and PD-L1), cytokine production, and the ability to stimulate allogenic CD4(+) T cell proliferation.

resultsBoth BDCA-1(+) and BDCA-3(+) mDCs were susceptible to infection with RSV and demonstrated enhanced expression of CD86, and the inhibitory costimulatory molecules CD80 and PD-L1. Compared to BDCA-3(+) mDCs, RSV-infected BDCA-1(+) mDC produced a profile of cytokines and chemokines predominantly associated with pro-inflammatory responses (IL-1β, IL-6, IL-12, MIP-1α, and TNF-α), and both BDCA-1(+) and BDCA-3(+) mDCs were found to produce IL-10. Compared to uninfected mDCs, RSV-infected BDCA-1(+) and BDCA-3(+) mDCs demonstrated a reduced capacity to stimulate T cell proliferation.

conclusionsRSV infection induces a distinct pattern of costimulatory molecule expression and cytokine production by BDCA-1(+) and BDCA-3(+) mDCs, and impairs their ability to stimulate T cell proliferation.The differential expression of CD86 and pro-inflammatory cytokines by highly purified mDC subsets in response to RSV provides further evidence that BDCA-1(+) and BDCA-3(+) mDCs have distinct roles in coordinating the host immune response during RSV infection. Findings of differential expression of PD-L1 and IL-10 by infected mDCs, suggests possible mechanisms by which RSV is able to impair adaptive immune responses.