title: Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcRgamma-Syk-Card9-dependent innate immune activation.
abstract: Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk-Card9-Bcl10-Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif-bearing adaptor protein Fc receptor gamma chain (FcRgamma). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk-Card9 pathway as a rational target for vaccine development against tuberculosis.
authors.affiliation: Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, D-81675 Munich, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Werninghaus
authors.forename: Anna
authors.initials: A
authors.lastname: Babiak
authors.forename: Olaf
authors.initials: O
authors.lastname: Gross
authors.forename: Christoph
authors.initials: C
authors.lastname: Hölscher
authors.forename: Harald
authors.initials: H
authors.lastname: Dietrich
authors.forename: Else Marie
authors.initials: EM
authors.lastname: Agger
authors.forename: Jörg
authors.initials: J
authors.lastname: Mages
authors.forename: Attila
authors.initials: A
authors.lastname: Mocsai
authors.forename: Hanne
authors.initials: H
authors.lastname: Schoenen
authors.forename: Katrin
authors.initials: K
authors.lastname: Finger
authors.forename: Falk
authors.initials: F
authors.lastname: Nimmerjahn
authors.forename: Gordon D
authors.initials: GD
authors.lastname: Brown
authors.forename: Carsten
authors.initials: C
authors.lastname: Kirschning
authors.forename: Antje
authors.initials: A
authors.lastname: Heit
authors.forename: Peter
authors.initials: P
authors.lastname: Andersen
authors.forename: Hermann
authors.initials: H
authors.lastname: Wagner
authors.forename: Jürgen
authors.initials: J
authors.lastname: Ruland
authors.forename: Roland
authors.initials: R
authors.lastname: Lang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000074018:B-Cell CLL-Lymphoma 10 Protein; D053468:CARD Signaling Adaptor Proteins; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D020169:Caspases / Q000235:genetics; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D006017:Glycolipids / Q000276:immunology / Q000494:pharmacology; D007113:Immunity, Innate / Q000276:immunology*; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008168:Lung / Q000276:immunology / Q000382:microbiology; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D017455:Receptors, IgE / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D000072377:Syk Kinase; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D032581:Tuberculosis Vaccines / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D014397:Tuberculosis, Pulmonary / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D000074018:B-Cell CLL-Lymphoma 10 Protein; C488088:Bcl10 protein, mouse; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; D016207:Cytokines; D006017:Glycolipids; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D017455:Receptors, IgE; D032581:Tuberculosis Vaccines; D022223:Vaccines, Subunit; C507803:trehalose 6,6'-dibehenate; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D020169:Caspases; C498509:Malt1 protein, mouse; D000074884:Mucosa-Associated Lymphoid Tissue Lymphoma Translocation 1 Protein