Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS

Laura J. Pallett (), Leo Swadling, Mariana Diniz, Alexander A. Maini, Marius Schwabenland, Adrià Dalmau Gasull, Jessica Davies, Stephanie Kucykowicz, Jessica K. Skelton, Niclas Thomas, Nathalie M. Schmidt, Oliver E. Amin, Upkar S. Gill, Kerstin A. Stegmann, Alice R. Burton, Emily Stephenson, Gary Reynolds, Matt Whelan, Jenifer Sanchez, Roel Maeyer, Clare Thakker, Kornelija Suveizdyte, Imran Uddin, Ana M. Ortega-Prieto, Charlotte Grant, Farid Froghi, Giuseppe Fusai, Sabela Lens, Sofia Pérez-del-Pulgar, Walid Al-Akkad, Giuseppe Mazza, Mahdad Noursadeghi, Arne Akbar, Patrick T. F. Kennedy, Brian R. Davidson, Marco Prinz, Benjamin M. Chain, Muzlifah Haniffa, Derek W. Gilroy, Marcus Dorner, Bertram Bengsch, Anna Schurich and Mala K. Maini ()
Additional contact information
Laura J. Pallett: University College London
Leo Swadling: University College London
Mariana Diniz: University College London
Alexander A. Maini: University College London
Marius Schwabenland: University of Freiburg
Adrià Dalmau Gasull: University of Freiburg
Jessica Davies: University College London
Stephanie Kucykowicz: University College London
Jessica K. Skelton: Imperial College London
Niclas Thomas: University College London
Nathalie M. Schmidt: University College London
Oliver E. Amin: University College London
Upkar S. Gill: Queen Mary University of London
Kerstin A. Stegmann: University College London
Alice R. Burton: University College London
Emily Stephenson: Newcastle University
Gary Reynolds: Newcastle University
Matt Whelan: University College London
Jenifer Sanchez: Kings College London
Roel Maeyer: University College London
Clare Thakker: University College London
Kornelija Suveizdyte: University College London
Imran Uddin: University College London
Ana M. Ortega-Prieto: Imperial College London
Charlotte Grant: University College London
Farid Froghi: University College London
Giuseppe Fusai: University College London
Sabela Lens: University College London
Sofia Pérez-del-Pulgar: University of Barcelona
Walid Al-Akkad: University College London
Giuseppe Mazza: University College London
Mahdad Noursadeghi: University College London
Arne Akbar: University College London
Patrick T. F. Kennedy: Queen Mary University of London
Brian R. Davidson: University College London
Marco Prinz: University of Freiburg
Benjamin M. Chain: University College London
Muzlifah Haniffa: Newcastle University
Derek W. Gilroy: University College London
Marcus Dorner: Imperial College London
Bertram Bengsch: University of Freiburg
Anna Schurich: University College London
Mala K. Maini: University College London

Nature, 2023, vol. 614, issue 7947, 334-342

Abstract: Abstract The liver is bathed in bacterial products, including lipopolysaccharide transported from the intestinal portal vasculature, but maintains a state of tolerance that is exploited by persistent pathogens and tumours1–4. The cellular basis mediating this tolerance, yet allowing a switch to immunity or immunopathology, needs to be better understood for successful immunotherapy of liver diseases. Here we show that a variable proportion of CD8+ T cells compartmentalized in the human liver co-stain for CD14 and other prototypic myeloid membrane proteins and are enriched in close proximity to CD14high myeloid cells in hepatic zone 2. CD14+CD8+ T cells preferentially accumulate within the donor pool in liver allografts, among hepatic virus-specific and tumour-infiltrating responses, and in cirrhotic ascites. CD14+CD8+ T cells exhibit increased turnover, activation and constitutive immunomodulatory features with high homeostatic IL-10 and IL-2 production ex vivo, and enhanced antiviral/anti-tumour effector function after TCR engagement. This CD14+CD8+ T cell profile can be recapitulated by the acquisition of membrane proteins—including the lipopolysaccharide receptor complex—from mononuclear phagocytes, resulting in augmented tumour killing by TCR-redirected T cells in vitro. CD14+CD8+ T cells express integrins and chemokine receptors that favour interactions with the local stroma, which can promote their induction through CXCL12. Lipopolysaccharide can also increase the frequency of CD14+CD8+ T cells in vitro and in vivo, and skew their function towards the production of chemotactic and regenerative cytokines. Thus, bacterial products in the gut–liver axis and tissue stromal factors can tune liver immunity by driving myeloid instruction of CD8+ T cells with immunomodulatory ability.

Date: 2023
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DOI: 10.1038/s41586-022-05645-6

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