Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome

Kevin Shenderov, Daniel L. Barber, Katrin D. Mayer-Barber, Sudagar S. Gurcha, Dragana Jankovic, Carl G. Feng, Sandy Oland, Sara Hieny, Pat Caspar, Sho Yamasaki, Xin Lin, Jenny P.Y. Ting, Giorgio Trinchieri, Gurdyal S. Besra, Vincenzo Cerundolo, Alan Sher

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    Abstract

    Although adjuvants are critical vaccine components, their modes of action are poorly understood. In this study, we investigated the mechanisms by which the heat-killed mycobacteria in CFA promote Th17 CD4+ T cell responses.We found that IL-17 secretion by CD4+ T cells following CFA immunization requires MyD88 and IL-1β/IL-1R signaling. Through measurement of Ag-specific responses after adoptive transfer of OTII cells, we confirmed that MyD88-dependent signaling controls Th17 differentiation rather than simply production of IL-17. Additional experiments showed that CFA-induced Th17 differentiation involves IL-1β processing by the inflammasome, as mice lacking caspase-1, ASC, or NLRP3 exhibit partially defective responses after immunization. Biochemical fractionation studies further revealed that peptidoglycan is the major component of heat-killed mycobacteria responsible for inflammasome activation. By assaying Il1b transcripts in the injection site skin of CFA-immunized mice, we found that signaling through the adaptor molecule caspase activation and recruitment domain 9 (CARD9) plays a major role in triggering pro-IL-1β expression. Moreover, we demonstrated that recognition of the mycobacterial glycolipid trehalose dimycolate (cord factor) by the C-type lectin receptor mincle partially explains this CARD9 requirement. Importantly, purified peptidoglycan and cord factor administered in mineral oil synergized to recapitulate the Th17-promoting activity of CFA, and, as expected, this response was diminished in caspase-1- and CARD9-deficient mice. Taken together, these findings suggest a general strategy for the rational design of Th17-skewing adjuvants by combining agonists of the CARD9 pathway with inflammasome activators.

    Original languageEnglish
    Pages (from-to)5722-5730
    Number of pages9
    JournalJournal of Immunology
    Volume190
    Issue number11
    DOIs
    Publication statusPublished - Jun 1 2013

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology

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  • Cite this

    Shenderov, K., Barber, D. L., Mayer-Barber, K. D., Gurcha, S. S., Jankovic, D., Feng, C. G., Oland, S., Hieny, S., Caspar, P., Yamasaki, S., Lin, X., Ting, J. P. Y., Trinchieri, G., Besra, G. S., Cerundolo, V., & Sher, A. (2013). Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome. Journal of Immunology, 190(11), 5722-5730. https://doi.org/10.4049/jimmunol.1203343