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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 publication

DOI

10.4049/jimmunol.1203343

Type

Journal article

Journal

J Immunol

Publication Date

01/06/2013

Volume

190

Pages

5722 - 5730

Keywords

Adaptor Proteins, Signal Transducing, Adjuvants, Immunologic, Animals, CARD Signaling Adaptor Proteins, Cell Differentiation, Cord Factors, Inflammasomes, Interleukin-1beta, Lectins, C-Type, Membrane Proteins, Mice, Mice, Knockout, Mycobacterium, Myeloid Differentiation Factor 88, Peptidoglycan, Receptors, Interleukin-1, Receptors, Interleukin-18, Signal Transduction, Th17 Cells, Toll-Like Receptors