title: Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome.
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.
authors: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. shenderovk@niaid.nih.gov
authors: Kevin
authors: K
authors: Shenderov
authors: Daniel L
authors: DL
authors: Barber
authors: Katrin D
authors: KD
authors: Mayer-Barber
authors: Sudagar S
authors: SS
authors: Gurcha
authors: Dragana
authors: D
authors: Jankovic
authors: Carl G
authors: CG
authors: Feng
authors: Sandy
authors: S
authors: Oland
authors: Sara
authors: S
authors: Hieny
authors: Pat
authors: P
authors: Caspar
authors: Sho
authors: S
authors: Yamasaki
authors: Xin
authors: X
authors: Lin
authors: Jenny P-Y
authors: JP
authors: Ting
authors: Giorgio
authors: G
authors: Trinchieri
authors: Gurdyal S
authors: GS
authors: Besra
authors: Vincenzo
authors: V
authors: Cerundolo
authors: Alan
authors: A
authors: Sher
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000276:Adjuvants, Immunologic; D000818:Animals; D053468:CARD Signaling Adaptor Proteins; D002454:Cell Differentiation / Q000276:immunology; D003311:Cord Factors / Q000276:immunology*; D058847:Inflammasomes / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009161:Mycobacterium / Q000737:chemistry / Q000276:immunology*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D010457:Peptidoglycan / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000378:metabolism; D053724:Receptors, Interleukin-18 / Q000378:metabolism; D015398:Signal Transduction; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; D053468:CARD Signaling Adaptor Proteins; C513280:Card9 protein, mouse; C113583:Clecsf8 protein, mouse; D003311:Cord Factors; D058847:Inflammasomes; D053583:Interleukin-1beta; D037181:Lectins, C-Type; D008565:Membrane Proteins; D053594:Myeloid Differentiation Factor 88; D010457:Peptidoglycan; D017472:Receptors, Interleukin-1; D053724:Receptors, Interleukin-18; D051193:Toll-Like Receptors
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