title: Double-negative T resident memory cells of the lung react to influenza virus infection via CD11c(hi) dendritic cells.
abstract: Immunity to Influenza A virus (IAV) is controlled by conventional TCRαβ(+) CD4(+) and CD8(+) T lymphocytes, which mediate protection or cause immunopathology. Here, we addressed the kinetics, differentiation, and antigen specificity of CD4(-)CD8(-) double-negative (DN) T cells. DNT cells expressed intermediate levels of TCR/CD3 and could be further divided in γδ T cells, CD1d-reactive type I NKT cells, NK1.1(+) NKT-like cells, and NK1.1(-) DNT cells. NK1.1(-) DNT cells had a separate antigen-specific repertoire in the steady-state lung, and expanded rapidly in response to IAV infection, irrespectively of the severity of infection. Up to 10% of DNT cells reacted to viral nucleoprotein. Reinfection experiments with heterosubtypic IAV revealed that viral replication was a major trigger for recruitment. Unlike conventional T cells, the NK1.1(-) DNT cells were in a preactivated state, expressing memory markers CD44, CD11a, CD103, and the cytotoxic effector molecule FasL. DNT cells resided in the lung parenchyma, protected from intravascular labeling with CD45 antibody. The recruitment and maintenance of CCR2(+) CCR5(+) CXCR3(+) NK1.1(-) DNT cells depended on CD11c(hi) dendritic cells (DCs). Functionally, DNT cells controlled the lung DC subset balance, suggesting they might act as immunoregulatory cells. In conclusion, we identify activation of resident memory NK1.1(-) DNT cells as an integral component of the mucosal immune response to IAV infection.
authors.affiliation: VIB Inflammation Research Center, Laboratory of Immunoregulation, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Neyt
authors.affiliation: Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: C H
authors.initials: CH
authors.lastname: GeurtsvanKessel
authors.affiliation: VIB Inflammation Research Center, Laboratory of Immunoregulation, Ghent, Belgium.|Department of Respiratory Medicine, Ghent University, Ghent, Belgium.|Department of Pulmonary Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: B N
authors.initials: BN
authors.lastname: Lambrecht
mesh_terms: D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D039521:CD11c Antigen / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D018928:Immunity, Mucosal; D007156:Immunologic Memory; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D039521:CD11c Antigen; D011948:Receptors, Antigen, T-Cell