Differential Response of Respiratory Dendritic Cell Subsets to Influenza Virus Infection

Abstract

Dendritic cells (DC) are believed to play an important role in the initiation of innate and adaptive immune responses to infection, including respiratory tract infections, where respiratory DC (RDC) perform this role.In this report, we examined the susceptibilities of isolated murine RDC to influenza virus infection in vitro and the effect of the multiplicity of infection (MOI) on costimulatory ligand upregulation and inflammatory cytokine/chemokine production after infection. We found that the efficiency of influenza virus infection of RDC increased with increasing MOIs. Furthermore, distinct subpopulations of RDC differed in their susceptibilities to influenza virus infection and in the magnitude/tempo of costimulatory ligand expression. Additional characterization of the CD11c-positive (CD11c DC produced elevated levels of the murine chemokine CXCL1 (KC), interleukin 12p40, and RANTES in response to influenza virus infection. Our results indicate that RDC are targets of influenza virus infection and that distinct RDC subsets differ in their susceptibilities and responses to infection.Dendritic cells (DC) are a distinct lineage of hematopoietic mononuclear cells that are believed to play a critical role in the induction of adaptive immune responses and may also serve a direct role as effector cells in the innate immune responses to infection (4,15,30). DC are found both within secondary lymphoid organs (e.g., the spleen and lymph nodes) and at peripheral sites/body surfaces (e.g., the gastrointestinal tract, the genitourinary tract, and the respiratory tract). DC localized to body surfaces act as sentinels, monitoring these sites for the presence of foreign antigen (in particular, infectious microorganisms). These peripheral DC capture antigen (by direct antigen uptake and/or infection of the DC) and, as a result of this encounter, undergo an activation/maturation process. The activated DC then transport the antigen from the body surface to secondary lymphoid organs, where the induction of the adaptive immune responses occurs (3, 16).DC isolated from secondary lymphoid organs or peripheral sites demonstrate considerable heterogeneity in both phenotype (i.e., cell surface marker expression) and function and can be categorized into distinct subsets. Both the number of distinct DC subsets and the distribution of these DC subsets can differ dramatically depending on the sites or tissues of origin (2,12,34).The respiratory tract (RT) is a major site of antigen encounters with DC. Respiratory DC (RDC) are distributed throughout the upper and lower RT. In the RT, RDC are localized to both large and small airways, as well as to the lung parenchyma (21, 33). Airway-resident RDC are intimately associated with the airway epithelium, are uniformly distributed along the airways, and have a relatively high turnover rate. By contrast, RDC found in alveoli and the lung parenchyma are less uniformly distributed and have a lower turnover rate than airwayassociated RDC (32). RDC have been divided into distinct subsets based on ...

Highly Pathogenic Influenza Virus Infection of the Thymus Interferes with T Lymphocyte Development

“…In our in vivo study, macrophages were not the major target for infection. More interestingly, it has been reported that DCs can be infected by influenza viruses in vitro (30). Because of the DC function to migrate continuously into the LN but also in the thymus (15) with or without having contact and being activated by an Ag, thymic DCs play a major role in establishing tolerance by negative selection of thymocytes and induction of Tregs (45).…”

“…RDCs were isolated as previously described (30). Briefly, alveolar macrophages were removed by incubating the counted cells with a PE-labeled anti-SiglecF Ab.…”

“…Isolation of DCs was performed as described previously (30). Mice were sacrificed, and lungs were perfused with 10 ml PBS.…”

Hematopoietic-specific targeting of influenza A virus reveals replication requirements for induction of antiviral immune responses

“…Within the draining LN, DC subsets, primarily CD103 + DCs that migrated from the infected respiratory tract, as well as LN resident CD8α + DCs, present antigen to CD8 T cells (14)(15)(16)(17)(18). These DCs can acquire IAV antigens by at least three distinct mechanisms: (i) through direct infection, (ii) through phagocytosis of necrotic or apoptotic IAV-infected epithelial cells, or (iii) through membrane exchange with infected cells and transfer of peptide-loaded MHC I (1)(2)(3)(4)(5)(6)(19)(20)(21)(22). Importantly, antigen presentation by CD103 + DCs and CD8α + DC subsets can be mediated by any one of these three processes (23)(24)(25).…”

“…However, IAV is also capable of infecting cells of the immune system, specifically antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages (1)(2)(3)(4)(5)(6). The body's defense to IAV infection requires a coordinated response from both the innate and adaptive arms of the immune system to control, and ultimately clear, the infection.…”