title: Differential response of BDCA-1+ and BDCA-3+ myeloid dendritic cells to respiratory syncytial virus infection.
abstract: BACKGROUND
  Respiratory 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.
  
  
  METHODS
  BDCA-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.
  
  
  RESULTS
  Both 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.
  
  
  CONCLUSIONS
  RSV 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.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA. megupta@utmb.edu
authors.forename: Meera R
authors.initials: MR
authors.lastname: Gupta
authors.forename: Deepthi
authors.initials: D
authors.lastname: Kolli
authors.forename: Roberto P
authors.initials: RP
authors.lastname: Garofalo
mesh_terms: D000328:Adult; D018949:Antigens, CD1; D000954:Antigens, Surface / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D005260:Female; D006023:Glycoproteins; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000473:pathology*; D018180:Thrombomodulin
chemical_list: D018949:Antigens, CD1; D000954:Antigens, Surface; C437944:CD1C protein, human; D016207:Cytokines; D006023:Glycoproteins; C546931:THBD protein, human; D018180:Thrombomodulin