期刊
JOURNAL OF IMMUNOLOGY
卷 190, 期 11, 页码 5722-5730出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1203343
关键词
-
类别
资金
- Intramural Research Program of the National Institute for Allergy and Infectious Diseases
- UK Medical Research Council
- Cancer Research UK [C399/A2291]
- Rhodes Trust
- Royal Society Wolfson Research Merit Award
- Medical Research Council
- Wellcome Trust [081569/Z/06/Z, 0849231B/08/Z]
- MRC [G1001750, MC_UU_12010/1, MR/K012118/1, G1001023] Funding Source: UKRI
- Cancer Research UK [11331] Funding Source: researchfish
- Medical Research Council [G1001750, G1001023, MC_UU_12010/1, MR/K012118/1] Funding Source: researchfish
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-1 beta/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-1 beta 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 Il lb 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-1 beta 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据