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

Kerstin Werninghaus, Anna Babiak, Olaf Gross, Christoph Hölscher, Harald Dietrich, Else Marie Agger, Jörg Mages, Attila Mocsai, Hanne Schoenen, Katrin Finger, Falk Nimmerjahn, Gordon D Brown, Carsten Kirschning, Antje Heit, Peter Andersen, Hermann Wagner, Jürgen Ruland, Roland Lang

Research output: Contribution to journalArticlepeer-review

267 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)89-97
Number of pages9
JournalJournal of Experimental Medicine
Issue number1
Publication statusPublished - 16 Jan 2009


  • adaptor proteins, signal transducing
  • adjuvants, immunologic
  • animals
  • CD4-positive T-lymphocytes
  • caspases
  • cytokines
  • dendritic cells
  • glycolipids
  • immunity, innate
  • immunoglobulin G
  • intracellular signaling peptides and proteins
  • lung
  • lymph nodes
  • macrophage activation
  • macrophages
  • mice
  • mice, inbred C57BL
  • mice, knockout
  • neoplasm proteins
  • protein-tyrosine kinases
  • receptors, IgE
  • signal transduction
  • t-lymphocytes, helper-inducer
  • tuberculosis vaccines
  • tuberculosis, pulmonary
  • vaccines, subunit


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