title: Age-Dependent Cell Trafficking Defects in Draining Lymph Nodes Impair Adaptive Immunity and Control of West Nile Virus Infection.
abstract: Impaired immune responses in the elderly lead to reduced vaccine efficacy and increased susceptibility to viral infections. Although several groups have documented age-dependent defects in adaptive immune priming, the deficits that occur prior to antigen encounter remain largely unexplored. Herein, we identify novel mechanisms for compromised adaptive immunity that occurs with aging in the context of infection with West Nile virus (WNV), an encephalitic flavivirus that preferentially causes disease in the elderly. An impaired IgM and IgG response and enhanced vulnerability to WNV infection during aging was linked to delayed germinal center formation in the draining lymph node (DLN). Adoptive transfer studies and two-photon intravital microscopy revealed a decreased trafficking capacity of donor naïve CD4+ T cells from old mice, which manifested as impaired T cell diapedesis at high endothelial venules and reduced cell motility within DLN prior to antigen encounter. Furthermore, leukocyte accumulation in the DLN within the first few days of WNV infection or antigen-adjuvant administration was diminished more generally in old mice and associated with a second aging-related defect in local cytokine and chemokine production. Thus, age-dependent cell-intrinsic and environmental defects in the DLN result in delayed immune cell recruitment and antigen recognition. These deficits compromise priming of early adaptive immune responses and likely contribute to the susceptibility of old animals to acute WNV infection.
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Richner
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Grzegorz B
authors.initials: GB
authors.lastname: Gmyrek
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Govero
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Yizheng
authors.initials: Y
authors.lastname: Tu
authors.affiliation: Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Gerritje J W
authors.initials: GJ
authors.lastname: van der Windt
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Talibah U
authors.initials: TU
authors.lastname: Metcalf
authors.affiliation: Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America.
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.affiliation: Department of Theoretical Biology & Bioinformatics, Utrecht University, Utrecht, Netherlands.
authors.forename: Johannes
authors.initials: J
authors.lastname: Textor
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Miller
authors.affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States of America; Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America; Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Diamond
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology*; D000375:Aging; D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology*; D001921:Brain / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology*; D051379:Mice; D014901:West Nile Fever / Q000276:immunology / Q000821:virology*; D014902:West Nile virus / Q000276:immunology / Q000302:isolation & purification*
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines