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NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner

Diniz, Mariana O; Schurich, Anna; Chinnakannan, Senthil K; Duriez, Marion; Stegmann, Kerstin A; Davies, Jessica; Kucykowicz, Stephanie; ... Maini, Mala K; + view all (2022) NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner. Science Translational Medicine , 14 (640) , Article eabi4670. 10.1126/scitranslmed.abi4670. Green open access

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Abstract

A better understanding of mechanisms that regulate CD8+T cell responses to therapeutic vaccines is needed to develop approaches to enhance vaccine efficacy for chronic viral infections and cancers. We show here that NK cell depletion enhanced antigen-specific T cell responses to chimp adenoviral vector (ChAdOx) vaccination in a mouse model of chronic HBV infection (CHB). Probing the mechanism underlying this negative regulation, we observed that CHB drove parallel up-regulation of programmed cell death ligand 1 (PD-L1) on liver-resident NK cells and programmed cell death 1 (PD-1) on intrahepatic T cells. PD-L1-expressing liver-resident NK cells suppressed PD-1hiCD8+T cells enriched within the HBV-specific response to therapeutic vaccination. Cytokine activation of NK cells also induced PD-L1, and combining cytokine activation with PD-L1 blockade resulted in conversion of NK cells into efficient helpers that boosted HBV-specific CD8+T cell responses to therapeutic vaccination in mice and to chronic infection in humans. Our findings delineate an immunotherapeutic combination that can boost the response to therapeutic vaccination in CHB and highlight the broader importance of PD-L1-dependent regulation of T cells by cytokine-activated NK cells.

Type: Article
Title: NK cells limit therapeutic vaccine-induced CD8+T cell immunity in a PD-L1-dependent manner
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.abi4670
Publisher version: https://doi.org/10.1126/scitranslmed.abi4670
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, T-CELLS, VIRAL-INFECTION, RESPONSES, IMMUNOTHERAPY, DEPLETION
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10150732
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