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, Shou Yamasaki, Xin Lin, Jenny P.Y. Ting, Giorgio Trinchieri, Gurdyal S. Besra, Vincenzo Cerundolo, Alan Sher

    Research output: Contribution to journalArticle

    68 Citations (Scopus)

    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

    Fingerprint

    Cord Factors
    Inflammasomes
    Peptidoglycan
    Mycobacterium
    Interleukin-1
    Caspase 1
    Interleukin-17
    Immunization
    Hot Temperature
    C-Type Lectins
    T-Lymphocytes
    Mineral Oil
    Adoptive Transfer
    Glycolipids
    Vaccines
    Skin
    Injections
    Caspase Activation and Recruitment Domain

    All Science Journal Classification (ASJC) codes

    • Immunology and Allergy
    • Immunology

    Cite this

    Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome. / Shenderov, Kevin; Barber, Daniel L.; Mayer-Barber, Katrin D.; Gurcha, Sudagar S.; Jankovic, Dragana; Feng, Carl G.; Oland, Sandy; Hieny, Sara; Caspar, Pat; Yamasaki, Shou; Lin, Xin; Ting, Jenny P.Y.; Trinchieri, Giorgio; Besra, Gurdyal S.; Cerundolo, Vincenzo; Sher, Alan.

    In: Journal of Immunology, Vol. 190, No. 11, 01.06.2013, p. 5722-5730.

    Research output: Contribution to journalArticle

    Shenderov, K, Barber, DL, Mayer-Barber, KD, Gurcha, SS, Jankovic, D, Feng, CG, Oland, S, Hieny, S, Caspar, P, Yamasaki, S, Lin, X, Ting, JPY, Trinchieri, G, Besra, GS, 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, vol. 190, no. 11, pp. 5722-5730. https://doi.org/10.4049/jimmunol.1203343
    Shenderov, Kevin ; Barber, Daniel L. ; Mayer-Barber, Katrin D. ; Gurcha, Sudagar S. ; Jankovic, Dragana ; Feng, Carl G. ; Oland, Sandy ; Hieny, Sara ; Caspar, Pat ; Yamasaki, Shou ; Lin, Xin ; Ting, Jenny P.Y. ; Trinchieri, Giorgio ; Besra, Gurdyal S. ; Cerundolo, Vincenzo ; Sher, Alan. / Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome. In: Journal of Immunology. 2013 ; Vol. 190, No. 11. pp. 5722-5730.
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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.",
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    AU - Barber, Daniel L.

    AU - Mayer-Barber, Katrin D.

    AU - Gurcha, Sudagar S.

    AU - Jankovic, Dragana

    AU - Feng, Carl G.

    AU - Oland, Sandy

    AU - Hieny, Sara

    AU - Caspar, Pat

    AU - Yamasaki, Shou

    AU - Lin, Xin

    AU - Ting, Jenny P.Y.

    AU - Trinchieri, Giorgio

    AU - Besra, Gurdyal S.

    AU - Cerundolo, Vincenzo

    AU - Sher, Alan

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