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Cord factor and peptidoglycan recapitulate the Th17-promoting adjuvant activity of mycobacteria through mincle/CARD9 signaling and the inflammasome.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2013 Jun 01; Vol. 190 (11), pp. 5722-30. Date of Electronic Publication: 2013 Apr 29. - Publication Year :
- 2013
-
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.
- Subjects :
- Adjuvants, Immunologic
Animals
CARD Signaling Adaptor Proteins
Cell Differentiation immunology
Inflammasomes metabolism
Interleukin-1beta metabolism
Mice
Mice, Knockout
Mycobacterium chemistry
Myeloid Differentiation Factor 88 metabolism
Receptors, Interleukin-1 metabolism
Receptors, Interleukin-18 metabolism
Signal Transduction
Th17 Cells cytology
Toll-Like Receptors metabolism
Adaptor Proteins, Signal Transducing metabolism
Cord Factors immunology
Lectins, C-Type metabolism
Membrane Proteins metabolism
Mycobacterium immunology
Peptidoglycan immunology
Th17 Cells immunology
Th17 Cells metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 190
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 23630357
- Full Text :
- https://doi.org/10.4049/jimmunol.1203343