title: Unique type I interferon responses determine the functional fate of migratory lung dendritic cells during influenza virus infection.
abstract: Migratory lung dendritic cells (DCs) transport viral antigen from the lungs to the draining mediastinal lymph nodes (MLNs) during influenza virus infection to initiate the adaptive immune response. Two major migratory DC subsets, CD103(+) DCs and CD11b(high) DCs participate in this function and it is not clear if these antigen presenting cell (APC) populations become directly infected and if so whether their activity is influenced by the infection. In these experiments we show that both subpopulations can become infected and migrate to the draining MLN but a difference in their response to type I interferon (I-IFN) signaling dictates the capacity of the virus to replicate. CD103(+) DCs allow the virus to replicate to significantly higher levels than do the CD11b(high) DCs, and they release infectious virus in the MLNs and when cultured ex-vivo. Virus replication in CD11b(high) DCs is inhibited by I-IFNs, since ablation of the I-IFN receptor (IFNAR) signaling permits virus to replicate vigorously and productively in this subset. Interestingly, CD103(+) DCs are less sensitive to I-IFNs upregulating interferon-induced genes to a lesser extent than CD11b(high) DCs. The attenuated IFNAR signaling by CD103(+) DCs correlates with their described superior antigen presentation capacity for naïve CD8(+) T cells when compared to CD11b(high) DCs. Indeed ablation of IFNAR signaling equalizes the competency of the antigen presenting function for the two subpopulations. Thus, antigen presentation by lung DCs is proportional to virus replication and this is tightly constrained by I-IFN. The "interferon-resistant" CD103(+) DCs may have evolved to ensure the presentation of viral antigens to T cells in I-IFN rich environments. Conversely, this trait may be exploitable by viral pathogens as a mechanism for systemic dissemination.
authors.affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, New York, United States of America. bruno.moltedo@mssm.edu
authors.forename: Bruno
authors.initials: B
authors.lastname: Moltedo
authors.forename: Wenjing
authors.initials: W
authors.lastname: Li
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Yount
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Moran
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000821:virology; D015703:Antigens, CD / Q000032:analysis; D000956:Antigens, Viral / Q000276:immunology; D039481:CD11b Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000472:pathogenicity / Q000502:physiology; D039001:Integrin alpha Chains / Q000032:analysis; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000821:virology; D017471:Receptors, Interferon / Q000037:antagonists & inhibitors; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; D000956:Antigens, Viral; D039481:CD11b Antigen; D039001:Integrin alpha Chains; D007370:Interferon Type I; D017471:Receptors, Interferon; C091367:alpha E integrins
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