期刊
ELIFE
卷 9, 期 -, 页码 -出版社
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.52668
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资金
- Medical Research Council [MR/P023754/1, MR/N006631/1, MR/S024220/1]
- Medical Research Innovation Grant 2017
- Wellcome Trust [210662/Z/18/Z, FC0010218, 203135, 104803]
- Bill and Melinda Gates Foundation [OPP1137006]
- Cancer Research UK [23562]
- UK Research and Innovation [FC0010218]
- National Institutes of Health [U19AI111276]
- National Institute for Health Research Academic Clinical Lectureship
- MRC [MR/S024220/1, MR/N006631/1, MR/P023754/1] Funding Source: UKRI
- Wellcome Trust [210662/Z/18/Z] Funding Source: Wellcome Trust
- Bill and Melinda Gates Foundation [OPP1137006] Funding Source: Bill and Melinda Gates Foundation
Previously, we developed a 3-dimensional cell culture model of human tuberculosis (TB) and demonstrated its potential to interrogate the host-pathogen interaction (Tezera et al., 2017a). Here, we use the model to investigate mechanisms whereby immune checkpoint therapy for cancer paradoxically activates TB infection. In patients, PD-1 is expressed in Mycobacterium tuberculosis (Mtb)-infected lung tissue but is absent in areas of immunopathology. In the microsphere model, PD-1 ligands are up-regulated by infection, and the PD-1/PD-L1 axis is further induced by hypoxia. Inhibition of PD-1 signalling increases Mtb growth, and augments cytokine secretion. TNF-alpha is responsible for accelerated Mtb growth, and TNF-alpha neutralisation reverses augmented Mtb growth caused by anti-PD-1 treatment. In human TB, pulmonary TNF-alpha immunoreactivity is increased and circulating PD-1 expression negatively correlates with sputum TNF-alpha concentrations. Together, our findings demonstrate that PD-1 regulates the immune response in TB, and inhibition of PD-1 accelerates Mtb growth via excessive TNF-alpha secretion.
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