title: Three phases of CD8 T cell response in the lung following H1N1 influenza infection and sphingosine 1 phosphate agonist therapy.
abstract: Influenza-induced lung edema and inflammation are exacerbated by a positive feedback loop of cytokine and chemokine production termed a 'cytokine storm', a hallmark of increased influenza-related morbidity and mortality. Upon infection, an immune response is rapidly initiated in the lungs and draining lymph node, leading to expansion of virus-specific effector cells. Using two-photon microscopy, we imaged the dynamics of dendritic cells (DC) and virus-specific eGFP(+)CD8(+) T cells in the lungs and draining mediastinal lymph nodes during the first two weeks following influenza infection. Three distinct phases of T cell and CD11c(+) DC behavior were revealed: 1) Priming, facilitated by the arrival of lung DCs in the lymph node and characterized by antigen recognition and expansion of antigen-specific CD8(+) T cells; asymmetric T cell division in contact with DCs was frequently observed. 2) Clearance, during which DCs re-populate the lung and T cells leave the draining lymph node and re-enter the lung tissue where enlarged, motile T cells come into contact with DCs and form long-lived interactions. 3) Maintenance, characterized by T-cell scanning of the lung tissue and dissociation from local antigen presenting cells; the T cells spend less time in association with DCs and migrate rapidly on collagen. A single dose of a sphingosine-1-phosphate receptor agonist, AAL-R, sufficient to suppress influenza-induced cytokine-storm, altered T cell and DC behavior during influenza clearance, delaying T cell division, cellular infiltration in the lung, and suppressing T-DC interactions in the lung. Our results provide a detailed description of T cell and DC choreography and dynamics in the lymph node and the lung during influenza infection. In addition, we suggest that phase lags in T cell and DC dynamics induced by targeting S1P receptors in vivo may attenuate the intensity of the immune response and can be manipulated for therapeutic benefit.
authors.affiliation: Department of Physiology and Biophysics and the Center for Immunology, University of California Irvine, Irvine, California, United States of America.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Matheu
authors.forename: John R
authors.initials: JR
authors.lastname: Teijaro
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Walsh
authors.forename: Milton L
authors.initials: ML
authors.lastname: Greenberg
authors.forename: David
authors.initials: D
authors.lastname: Marsolais
authors.forename: Ian
authors.initials: I
authors.lastname: Parker
authors.forename: Hugh
authors.initials: H
authors.lastname: Rosen
authors.forename: Michael B A
authors.initials: MB
authors.lastname: Oldstone
authors.forename: Michael D
authors.initials: MD
authors.lastname: Cahalan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D039521:CD11c Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism* / Q000502:physiology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology; D005434:Flow Cytometry; D053118:Influenza A Virus, H1N1 Subtype / Q000472:pathogenicity*; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D008246:Lysophospholipids / Q000819:agonists*; D051379:Mice; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D013110:Sphingosine / Q000819:agonists / Q000031:analogs & derivatives*
chemical_list: D000998:Antiviral Agents; D039521:CD11c Antigen; D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D013110:Sphingosine