title: Invariant natural killer T cells act as an extravascular cytotoxic barrier for joint-invading Lyme Borrelia.
abstract: CXCR6-GFP(+) cells, which encompass 70% invariant natural killer T cells (iNKT cells), have been found primarily patrolling inside blood vessels in the liver. Although the iNKT cells fail to interact with live pathogens, they do respond to bacterial glycolipids presented by CD1d on liver macrophage that have caught the microbe. In contrast, in this study using dual laser multichannel spinning-disk intravital microscopy of joints, the CXCR6-GFP, which also made up 60-70% iNKT cells, were not found in the vasculature but rather closely apposed to and surrounding the outside of blood vessels, and to a lesser extent throughout the extravascular space. These iNKT cells also differed in behavior, responding rapidly and directly to joint-homing pathogens like Borrelia burgdorferi, which causes Lyme disease. These iNKT cells interacted with B. burgdorferi at the vessel wall and disrupted dissemination attempts by these microbes into joints. Successful penetrance of B. burgdorferi out of the vasculature and into the joint tissue was met by a lethal attack by extravascular iNKT cells through a granzyme-dependent pathway, an observation also made in vitro for iNKT cells from joint but not liver or spleen. These results suggest a novel, critical extravascular iNKT cell immune surveillance in joints that functions as a cytotoxic barrier and explains a large increase in pathogen burden of B. burgdorferi in the joint of iNKT cell-deficient mice, and perhaps the greater susceptibility of humans to this pathogen because of fewer iNKT cells in human joints.
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Physiology and Pharmacology.
authors.forename: Woo-Yong
authors.initials: WY
authors.lastname: Lee
authors.affiliation: Department of Pharmacology, Faculty of Medicine, and Institute of Health Research, INCLIVA, University of Valencia, E46010 Valencia, Spain; and.
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Sanz
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Physiology and Pharmacology.
authors.forename: Connie H Y
authors.initials: CH
authors.lastname: Wong
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Microbiology and Infectious Diseases.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Hardy
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Biochemistry and Molecular Biology.
authors.forename: Aydan
authors.initials: A
authors.lastname: Salman-Dilgimen
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Biochemistry and Molecular Biology.
authors.forename: Tara J
authors.initials: TJ
authors.lastname: Moriarty
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Microbiology and Infectious Diseases, Department of Biochemistry and Molecular Biology.
authors.forename: George
authors.initials: G
authors.lastname: Chaconas
authors.affiliation: Clinical Studies Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Adriana
authors.initials: A
authors.lastname: Marques
authors.affiliation: Department of Surgery, Department of Cell Biology and Anatomy.
authors.forename: Roman
authors.initials: R
authors.lastname: Krawetz
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Microbiology and Infectious Diseases, Department of Internal Medicine, and.
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Mody
authors.affiliation: Calvin, Phoebe, and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Physiology and Pharmacology, pkubes@ucalgary.ca.
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000818:Animals; D025065:Borrelia burgdorferi / Q000276:immunology*; D053804:Granzymes / Q000235:genetics / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007592:Joint Diseases / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D007596:Joints / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D008099:Liver / Q000276:immunology / Q000473:pathology; D008193:Lyme Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000473:pathology; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000276:immunology / Q000473:pathology
chemical_list: D053804:Granzymes
keywords: Lyme arthritis; granzyme B; joint iNKT cells