Cutting edge: Mincle is essential for recognition and adjuvanticity of the mycobacterial cord factor and its synthetic analog trehalose-dibehenate.
The mycobacterial cord factor trehalose-6,6-dimycolate (TDM) and its synthetic analog trehalose-6,6-dibehenate (TDB) are potent adjuvants for Th1/Th17 vaccination that activate Syk-Card9 signaling in APCs. In this study, we have further investigated the molecular mechanism of innate immune activation by TDM and TDB. The Syk-coupling adapter protein FcRgamma was essential for macrophage activation and Th17 adjuvanticity. The FcRgamma-associated C-type lectin receptor Mincle was expressed in macrophages and upregulated by TDM and TDB. Recombinant Mincle-Fc fusion protein specifically bound to the glycolipids. Genetic ablation of Mincle abolished TDM/TDB-induced macrophage activation and induction of T cell immune responses to a tuberculosis subunit vaccine. Macrophages lacking Mincle or FcRgamma were impaired in the inflammatory response to Mycobacterium bovis bacillus Calmette-Guérin. These results establish that Mincle is a key receptor for the mycobacterial cord factor and controls the Th1/Th17 adjuvanticity of TDM and TDB.
Schoenen
Hanne
H
Institute of Clinical Microbiology, Immunology and Hygiene Medical Department, Friedrich-Alexander-Universität Erlangen-Nürnberg and University Clinics of Erlangen, Erlangen, Germany.
Bodendorfer
Barbara
B
Hitchens
Kelly
K
Manzanero
Silvia
S
Werninghaus
Kerstin
K
Nimmerjahn
Falk
F
Agger
Else Marie
EM
Stenger
Steffen
S
Andersen
Peter
P
Ruland
Jürgen
J
Brown
Gordon D
GD
Wells
Christine
C
Lang
Roland
R
D000276:Adjuvants, Immunologic / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D003311:Cord Factors / Q000276:immunology / Q000378:metabolism*; D006017:Glycolipids / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000096:biosynthesis / Q000502:physiology; D037181:Lectins, C-Type / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology / Q000378:metabolism*; D017452:Receptors, IgG / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013211:Staphylococcus aureus / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; C113583:Clecsf8 protein, mouse; D003311:Cord Factors; C485701:Fcgr1 protein, mouse; D006017:Glycolipids; C098680:Il17a protein, mouse; D020381:Interleukin-17; D037181:Lectins, C-Type; D008565:Membrane Proteins; D017452:Receptors, IgG; C507803:trehalose 6,6'-dibehenate