期刊
CELL REPORTS
卷 33, 期 9, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.108468
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资金
- Spanish Ministerio de Ciencia e Innovacion (MICINN)
- Agencia Estatal de Investigacion
- Fondo Europeo de Desarrollo Regional [RTI2018-094484-B-I00, RYC-2016-19463]
- FPU from the Spanish Ministry of Education, Culture and Sports [FPU16/03142]
- EMBO Long-Term Fellowship [EMBO LTF 463-2019]
Intracellular pathogens have evolved strategies to evade detection by cytotoxic CD8(+) T lymphocytes (CTLs). Here, we ask whether Leishmania parasites trigger the SHP-1-FcRg chain inhibitory axis to dampen antigen cross-presentation in dendritic cells expressing the C-type lectin receptor Mincle. We find increased cross-priming of CTLs in Leishmania-infected mice deficient for Mincle or with a selective loss of SHP-1 in CD11c(+) cells. The latter also shows improved cross-presentation of cell-associated viral antigens. CTL activation in vitro reveals increased MHC class I-peptide complex expression in Mincle- or SHP-1-deficient CD11c(+) cells. Neuraminidase treatment also boosts cross-presentation, suggesting that Leishmania triggers SHP1-associated sialic-acid-binding receptors. Mechanistically, enhanced antigen processing correlates with reduced endosomal acidification in the absence of SHP-1. Finally, we demonstrate that SHP-1 inhibition improves CD11c(+) cell-based vaccination against the parasite. Thus, SHP-1-mediated impairment of cross-presentation can be exploited by pathogens to evade CTLs, and SHP-1 inhibition improves CTL responses during vaccination.
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