期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 52, 期 3, 页码 431-446出版社
WILEY
DOI: 10.1002/eji.202149577
关键词
immunogenomics; innate immune memory; KDM4; QTL mapping; trained immunity
类别
资金
- ERC Advanced Grant [833247]
- Netherlands Organization for Scientific Research (NWO)
- VENI grant [863.13.011]
- NWO Spinoza prize [NWO SPI 92-266]
- European Research Council (ERC) [2012-322698]
- European Union [667837]
- NHMRC (Australia) CJ Martin Fellowship
- VENI [016.176.006]
Innate immune cells can develop memory characteristics through trained immunity. Host factors that affect the intensity of individual trained immunity responses are still largely unknown. This study identified key genes that influence trained immunity responses and highlighted the important roles of metabolic and epigenetic processes in regulating these responses.
Innate immune cells are able to build memory characteristics via a process termed trained immunity. Host factors that influence the magnitude of the individual trained immunity response remain largely unknown. Using an integrative genomics approach, our study aimed to prioritize and understand the role of specific genes in trained immunity responses. In vitro-induced trained immunity responses were assessed in two independent population-based cohorts of healthy individuals, the 300 Bacillus Calmette-Guerin (300BCG; n = 267) and 200 Functional Genomics (200FG; n = 110) cohorts from the Human Functional Genomics Project. Genetic loci that influence cytokine responses upon trained immunity were identified by conducting a meta-analysis of QTLs identified in the 300BCG and 200FG cohorts. From the identified QTL loci, we functionally validated the role of PI3K-Akt signaling pathway and two genes that belong to the family of Siglec receptors (Siglec-5 and Siglec-14). Furthermore, we identified the H3K9 histone demethylases of the KDM4 family as major regulators of trained immunity responses. These data pinpoint an important role of metabolic and epigenetic processes in the regulation of trained immunity responses, and these findings may open new avenues for vaccine design and therapeutic interventions.
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