title: Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy.
abstract: The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4+T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4+T-cell responses. In addition, activating endogenous host CD103+DCs and the CD40-CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4+T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks in TB vaccine efficacy.
authors.affiliation: Department of Molecular Microbiology, Washington University in St Louis, 660 S Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Kristin L
authors.identifier: 0000-0002-6008-2955
authors.initials: KL
authors.lastname: Griffiths
authors.affiliation: Department of Molecular Microbiology, Washington University in St Louis, 660 S Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Mushtaq
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Molecular Microbiology, Washington University in St Louis, 660 S Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Shibali
authors.initials: S
authors.lastname: Das
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Radha
authors.initials: R
authors.lastname: Gopal
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: William
authors.initials: W
authors.lastname: Horne
authors.affiliation: Witebsky Center for Microbial Pathogenesis &Immunology, Department of Microbiology &Immunology, University at Buffalo, 3435 Main Street, Buffalo, New York 14214, USA.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Connell
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, 500 Main Street, Cambridge, Massachusetts 02139, USA.
authors.forename: Kelly D
authors.identifier: 0000-0001-6200-7863
authors.initials: KD
authors.lastname: Moynihan
authors.affiliation: Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of UPMC, 4401 Penn Avenue, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Jay K
authors.initials: JK
authors.lastname: Kolls
authors.affiliation: Department of Materials Science and Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Darrell J
authors.initials: DJ
authors.lastname: Irvine
authors.affiliation: Division of Immunobiology, Washington University in St Louis, 660 S Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Maxim N
authors.initials: MN
authors.lastname: Artyomov
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, New York 14642, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Rangel-Moreno
authors.affiliation: Department of Molecular Microbiology, Washington University in St Louis, 660 S Euclid Avenue, St Louis, Missouri 63110, USA.
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D006801:Humans; D039001:Integrin alpha Chains / Q000378:metabolism; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology; D032581:Tuberculosis Vaccines / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D032581:Tuberculosis Vaccines; C091367:alpha E integrins