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 De maeyerClare 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, Mala K. Maini

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

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 tumours 1–4. 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 CD14 high 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.

Original languageEnglish
Pages (from-to)334-342
Number of pages9
JournalNature
Volume614
Issue number7947
Early online date25 Jan 2023
DOIs
Publication statusPublished - 9 Feb 2023

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