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Adjuvanticity of a synthetic cord factor analogue for subunit Mycobacterium tuberculosis vaccination requires FcR–Syk–Card9–dependent innate immune activation

¹ Institute of Medical Microbiology, Immunology and Hygiene, Technical University Munich, D-81675 Munich, Germany
² Department of Hematology, Technical University Munich, 80333 Munich, Germany
³ Division of Infection Immunology, Research Center Borstel, D-23845 Borstel, Germany
⁴ Adjuvant Research, Department of Infectious Disease Immunology, Statens Serum Institute, 2300 Copenhagen, Denmark
⁵ Semmelweis University School of Medicine, Budapest H-1089, Hungary
⁶ Molecular Medicine, ⁷ Institute of Clinical Microbiology, University Hospital Erlangen, 91054 Erlangen, Germany
⁸ Division of Immunology, CLS, Institute for Infectious Diseases and Molecular Medicine, University of Cape Town, 7925 Cape Town, South Africa

CORRESPONDENCE Roland Lang: Roland.Lang{at}uk-erlangen.de OR Jürgen Ruland: jruland{at}lrz.tum.de

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 chain (FcR). 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.

© 2009 Werninghaus et al.
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