期刊
PLOS BIOLOGY
卷 18, 期 6, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pbio.3000644
关键词
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资金
- Swedish Research Council [2015-00174, 2016-03052]
- Marie Sklodowska Curie Actions [INCA 600398]
- Jonas Soderquist Foundation for Virology and Immunology
- Petrus and Augusta Hedlund Foundation
- Swedish Cancer Society [CAN 2017/777]
- Center for Innovative Medicine Grant [20190732]
- National Institutes of Health [R01DK108350]
- CoSTAR-HS ARG Seed Fund [2018/02]
- NMRC Collaborative centre grant [NMRC/CG/C005B/2017_SGH]
- Karolinska Institutet Doctoral Grant
- Erik and Edith Fernstrom Foundation for Medical Research
- Swedish Research Council
- Stockholm County Council
- Scandinavian Society for Antimicrobial Chemotherapy
- Swedish Foundation for Antimicrobial Resistance
- Karolinska Institutet
- ARC grant [CE140100011]
- NHMRC SPR Fellowship [1117017]
Mucosa-associated invariant T (MAIT) cells are abundant antimicrobial T cells in humans and recognize antigens derived from the microbial riboflavin biosynthetic pathway presented by the MHC-Ib-related protein (MR1). However, the mechanisms responsible for MAIT cell antimicrobial activity are not fully understood, and the efficacy of these mechanisms against antibiotic resistant bacteria has not been explored. Here, we show that MAIT cells mediate MR1-restricted antimicrobial activity against Escherichia coli clinical strains in a manner dependent on the activity of cytolytic proteins but independent of production of pro-inflammatory cytokines or induction of apoptosis in infected cells. The combined action of the pore-forming antimicrobial protein granulysin and the serine protease granzyme B released in response to T cell receptor (TCR)-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living, extracellular forms of E. coli. Furthermore, MAIT cell-mediated bacterial control extends to multidrug-resistant E. coli primary clinical isolates additionally resistant to carbapenems, a class of last resort antibiotics. Notably, high levels of granulysin and granzyme B in the MAIT cell secretomes directly damage bacterial cells by increasing their permeability, rendering initially resistant E. coli susceptible to the bactericidal activity of carbapenems. These findings define the role of cytolytic effector proteins in MAIT cell-mediated antimicrobial activity and indicate that granulysin and granzyme B synergize to restore carbapenem bactericidal activity and overcome carbapenem resistance in E. coli.
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