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 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; Mala K. Maini

doi:10.1038/s41586-022-05645-6

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 journal › Article › peer-review

2 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 language	English
Pages (from-to)	334-342
Number of pages	9
Journal	Nature
Volume	614
Issue number	7947
Early online date	25 Jan 2023
DOIs	https://doi.org/10.1038/s41586-022-05645-6
Publication status	Published - 9 Feb 2023

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Pallett, L. J., Swadling, L., Diniz, M., Maini, A. A., Schwabenland, M., Gasull, A. D., Davies, J., Kucykowicz, S., Skelton, J. K., Thomas, N., Schmidt, N. M., Amin, O. E., Gill, U. S., Stegmann, K. A., Burton, A. R., Stephenson, E., Reynolds, G., Whelan, M., Sanchez, J., ... Maini, M. K. (2023). Tissue CD14⁺CD8⁺ T cells reprogrammed by myeloid cells and modulated by LPS. Nature, 614(7947), 334-342. https://doi.org/10.1038/s41586-022-05645-6

@article{a6929b217e4a4e12bc31b2367cddb666,

title = "Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS",

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.",

author = "Pallett, {Laura J.} and Leo Swadling and Mariana Diniz and Maini, {Alexander A.} and Marius Schwabenland and Gasull, {Adri{\`a} Dalmau} and Jessica Davies and Stephanie Kucykowicz and Skelton, {Jessica K.} and Niclas Thomas and Schmidt, {Nathalie M.} and Amin, {Oliver E.} and Gill, {Upkar S.} and Stegmann, {Kerstin A.} and Burton, {Alice R.} and Emily Stephenson and Gary Reynolds and Matt Whelan and Jenifer Sanchez and {De maeyer}, Roel and Clare Thakker and Kornelija Suveizdyte and Imran Uddin and Ortega-Prieto, {Ana M.} and Charlotte Grant and Farid Froghi and Giuseppe Fusai and Sabela Lens and Sofia P{\'e}rez-Del-Pulgar and Walid Al-Akkad and Giuseppe Mazza and Mahdad Noursadeghi and Arne Akbar and Kennedy, {Patrick T. F.} and Davidson, {Brian R.} and Marco Prinz and Chain, {Benjamin M.} and Muzlifah Haniffa and Gilroy, {Derek W.} and Marcus Dorner and Bertram Bengsch and Anna Schurich and Maini, {Mala K.}",

note = "Funding Information: We thank all of the patients and control volunteers who participated in this study, and all of the clinical staff who helped with participant recruitment, including the members of the Tissue Access for Patient Benefit Initiative at The Royal Free Hospital; H. Stauss for his suggestions; D. Dixon for help with the cytospin microscopy; the support staff at the UCL Infection and Immunity Flow Cytometry Core Facility; and P. S. Chana for his help with the imaging cytometry analysis. This work was funded by Wellcome Investigator Awards (101849/Z/13/A and 214191/Z/18/Z), a Medical Research Council grant (G0801213), a CRUK Immunology grant (26603) and a Hunter Accelerator award to M.K.M.; a UKRI Future Leader Fellowship to L.J.P.; a Medical Research Foundation grant to L.S.; a Wellcome Clinical Research Training Fellowship to U.S.G. (107389/Z/15/Z); a European Research Council H2020 Starter grant (ERC-StG-2015-637304) and the Wellcome New Investigator award (104771/A/14/Z) to M. Dorner; and the Berta Ottenstein Programme and IMM-PACT-Programme for Clinician Scientists, University of Freiburg funded by the Deutsche Forschungsgemeinschaft 413517907 to M.S. Funding Information: We thank all of the patients and control volunteers who participated in this study, and all of the clinical staff who helped with participant recruitment, including the members of the Tissue Access for Patient Benefit Initiative at The Royal Free Hospital; H. Stauss for his suggestions; D. Dixon for help with the cytospin microscopy; the support staff at the UCL Infection and Immunity Flow Cytometry Core Facility; and P. S. Chana for his help with the imaging cytometry analysis. This work was funded by Wellcome Investigator Awards (101849/Z/13/A and 214191/Z/18/Z), a Medical Research Council grant (G0801213), a CRUK Immunology grant (26603) and a Hunter Accelerator award to M.K.M.; a UKRI Future Leader Fellowship to L.J.P.; a Medical Research Foundation grant to L.S.; a Wellcome Clinical Research Training Fellowship to U.S.G. (107389/Z/15/Z); a European Research Council H2020 Starter grant (ERC-StG-2015-637304) and the Wellcome New Investigator award (104771/A/14/Z) to M. Dorner; and the Berta Ottenstein Programme and IMM-PACT-Programme for Clinician Scientists, University of Freiburg funded by the Deutsche Forschungsgemeinschaft 413517907 to M.S. Funding Information: M.K.M. and L.J.P. have received project funding from Gilead for research unrelated to this manuscript. M.K.M. has sat on advisory boards/provided consultancy for Gilead, Roche, GSK and VirBiosciences. L.J.P. has sat on advisory boards/provided consultancy for Gilead and SQZ Biotech. M.K.M. and L.J.P. have a patent application P116607GB filed through UCL-Business on the use of CD14CD8 T cells. + + Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = feb,

day = "9",

doi = "10.1038/s41586-022-05645-6",

language = "English",

volume = "614",

pages = "334--342",

journal = "Nature",

issn = "0028-0836",

publisher = "Springer Nature",

number = "7947",

}

Pallett, LJ, Swadling, L, Diniz, M, Maini, AA, Schwabenland, M, Gasull, AD, Davies, J, Kucykowicz, S, Skelton, JK, Thomas, N, Schmidt, NM, Amin, OE, Gill, US, Stegmann, KA, Burton, AR, Stephenson, E, Reynolds, G, Whelan, M, Sanchez, J, De maeyer, R, Thakker, C, Suveizdyte, K, Uddin, I, Ortega-Prieto, AM, Grant, C, Froghi, F, Fusai, G, Lens, S, Pérez-Del-Pulgar, S, Al-Akkad, W, Mazza, G, Noursadeghi, M, Akbar, A, Kennedy, PTF, Davidson, BR, Prinz, M, Chain, BM, Haniffa, M, Gilroy, DW, Dorner, M, Bengsch, B, Schurich, A & Maini, MK 2023, 'Tissue CD14⁺CD8⁺ T cells reprogrammed by myeloid cells and modulated by LPS', Nature, vol. 614, no. 7947, pp. 334-342. https://doi.org/10.1038/s41586-022-05645-6

TY - JOUR

T1 - Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS

AU - Pallett, Laura J.

AU - Swadling, Leo

AU - Diniz, Mariana

AU - Maini, Alexander A.

AU - Schwabenland, Marius

AU - Gasull, Adrià Dalmau

AU - Davies, Jessica

AU - Kucykowicz, Stephanie

AU - Skelton, Jessica K.

AU - Thomas, Niclas

AU - Schmidt, Nathalie M.

AU - Amin, Oliver E.

AU - Gill, Upkar S.

AU - Stegmann, Kerstin A.

AU - Burton, Alice R.

AU - Stephenson, Emily

AU - Reynolds, Gary

AU - Whelan, Matt

AU - Sanchez, Jenifer

AU - De maeyer, Roel

AU - Thakker, Clare

AU - Suveizdyte, Kornelija

AU - Uddin, Imran

AU - Ortega-Prieto, Ana M.

AU - Grant, Charlotte

AU - Froghi, Farid

AU - Fusai, Giuseppe

AU - Lens, Sabela

AU - Pérez-Del-Pulgar, Sofia

AU - Al-Akkad, Walid

AU - Mazza, Giuseppe

AU - Noursadeghi, Mahdad

AU - Akbar, Arne

AU - Kennedy, Patrick T. F.

AU - Davidson, Brian R.

AU - Prinz, Marco

AU - Chain, Benjamin M.

AU - Haniffa, Muzlifah

AU - Gilroy, Derek W.

AU - Dorner, Marcus

AU - Bengsch, Bertram

AU - Schurich, Anna

AU - Maini, Mala K.

N1 - Funding Information: We thank all of the patients and control volunteers who participated in this study, and all of the clinical staff who helped with participant recruitment, including the members of the Tissue Access for Patient Benefit Initiative at The Royal Free Hospital; H. Stauss for his suggestions; D. Dixon for help with the cytospin microscopy; the support staff at the UCL Infection and Immunity Flow Cytometry Core Facility; and P. S. Chana for his help with the imaging cytometry analysis. This work was funded by Wellcome Investigator Awards (101849/Z/13/A and 214191/Z/18/Z), a Medical Research Council grant (G0801213), a CRUK Immunology grant (26603) and a Hunter Accelerator award to M.K.M.; a UKRI Future Leader Fellowship to L.J.P.; a Medical Research Foundation grant to L.S.; a Wellcome Clinical Research Training Fellowship to U.S.G. (107389/Z/15/Z); a European Research Council H2020 Starter grant (ERC-StG-2015-637304) and the Wellcome New Investigator award (104771/A/14/Z) to M. Dorner; and the Berta Ottenstein Programme and IMM-PACT-Programme for Clinician Scientists, University of Freiburg funded by the Deutsche Forschungsgemeinschaft 413517907 to M.S. Funding Information: We thank all of the patients and control volunteers who participated in this study, and all of the clinical staff who helped with participant recruitment, including the members of the Tissue Access for Patient Benefit Initiative at The Royal Free Hospital; H. Stauss for his suggestions; D. Dixon for help with the cytospin microscopy; the support staff at the UCL Infection and Immunity Flow Cytometry Core Facility; and P. S. Chana for his help with the imaging cytometry analysis. This work was funded by Wellcome Investigator Awards (101849/Z/13/A and 214191/Z/18/Z), a Medical Research Council grant (G0801213), a CRUK Immunology grant (26603) and a Hunter Accelerator award to M.K.M.; a UKRI Future Leader Fellowship to L.J.P.; a Medical Research Foundation grant to L.S.; a Wellcome Clinical Research Training Fellowship to U.S.G. (107389/Z/15/Z); a European Research Council H2020 Starter grant (ERC-StG-2015-637304) and the Wellcome New Investigator award (104771/A/14/Z) to M. Dorner; and the Berta Ottenstein Programme and IMM-PACT-Programme for Clinician Scientists, University of Freiburg funded by the Deutsche Forschungsgemeinschaft 413517907 to M.S. Funding Information: M.K.M. and L.J.P. have received project funding from Gilead for research unrelated to this manuscript. M.K.M. has sat on advisory boards/provided consultancy for Gilead, Roche, GSK and VirBiosciences. L.J.P. has sat on advisory boards/provided consultancy for Gilead and SQZ Biotech. M.K.M. and L.J.P. have a patent application P116607GB filed through UCL-Business on the use of CD14CD8 T cells. + + Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/2/9

Y1 - 2023/2/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85146898237&partnerID=8YFLogxK

U2 - 10.1038/s41586-022-05645-6

DO - 10.1038/s41586-022-05645-6

M3 - Article

SN - 0028-0836

VL - 614

SP - 334

EP - 342

JO - Nature

JF - Nature

IS - 7947

ER -

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

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