Expression of E-cadherin by CD8+ T cells promotes their invasion into biliary epithelial cells

Scott P. Davies; Vincenzo Ronca; Grace E. Wootton; Natalia M. Krajewska; Amber G. Bozward; Rémi Fiancette; Daniel A. Patten; Katharina Yankouskaya; Gary M. Reynolds; Sofia Pat; Daniel C. Osei-Bordom; Naomi Richardson; Liam M. Grover; Christopher J. Weston; Ye H. Oo

doi:10.1038/s41467-024-44910-2

Expression of E-cadherin by CD8⁺ T cells promotes their invasion into biliary epithelial cells

Scott P. Davies^*, Vincenzo Ronca, Grace E. Wootton, Natalia M. Krajewska, Amber G. Bozward, Rémi Fiancette, Daniel A. Patten, Katharina Yankouskaya, Gary M. Reynolds, Sofia Pat, Daniel C. Osei-Bordom, Naomi Richardson, Liam M. Grover, Christopher J. Weston, Ye H. Oo^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

17 Downloads (Pure)

Abstract

The presence of CD8⁺ T cells in the cytoplasm of biliary epithelial cells (BEC) has been correlated with biliary damage associated with primary biliary cholangitis (PBC). Here, we characterise the mechanism of CD8⁺ T cell invasion into BEC. CD8⁺ T cells observed within BEC were large, eccentric, and expressed E-cadherin, CD103 and CD69. They were also not contained within secondary vesicles. Internalisation required cytoskeletal rearrangements which facilitated contact with BEC. Internalised CD8⁺ T cells were observed in both non-cirrhotic and cirrhotic diseased liver tissues but enriched in PBC patients, both during active disease and at the time of transplantation. E-cadherin expression by CD8⁺ T cells correlated with frequency of internalisation of these cells into BEC. E-cadherin⁺ CD8⁺ T cells formed β-catenin-associated interactions with BEC, were larger than E-cadherin- CD8⁺ T cells and invaded into BEC more frequently. Overall, we unveil a distinct cell-in-cell structure process in the liver detailing the invasion of E-cadherin⁺ CD103⁺ CD69⁺ CD8⁺ T cells into BEC.

Original language	English
Article number	853
Number of pages	22
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-44910-2
Publication status	Published - 29 Jan 2024

Bibliographical note

Acknowledgements:
The authors are grateful to all patients and donors at the Queen Elizabeth Hospital Birmingham, UK. We would like to thank the whole liver transplantation unit and all the clinical pathology team at the Queen Elizabeth Hospital for sample allocation; and all clinical staff who helped with patient recruitment. Additionally, we would like to thank the NHS team of Daniel Kearns, Janine Fear, Kulvinder Gill and Miriama Havrilova for their continued efforts in managing tissue access at the Centre for Liver and Gastrointestinal Research. We further thank Ms. Havrilova for her time taken to optimise immunohistochemistry stains for our investigation. We also gratefully acknowledge the contribution to this study made by the University of Birmingham’s Human Biomaterials Resource Centre (HBRC) which has been supported through Birmingham Science City - Experimental Medicine Network of Excellence project. The authors would like to acknowledge the Microscopy Facility at the University of Birmingham for support with confocal microscopy experiments, as well as Birmingham Advanced Light Microscopy facility (BALM) for support with super-resolution and high-content imaging. The authors would also like to acknowledge the University of Birmingham Flow Cytometry Services for assistance with flow cytometry and flow activated cell sorting. All electron microscopy was performed at the Centre for Electron Microscopy, Department of Metallurgy and Materials, University of Birmingham; we gratefully acknowledge their support and assistance in the completion of this project, with particular thanks to Theresa Morris for her help with sample preparation and instrument setup. We give thanks to Bethany Hope James and Dr. Kelly Chiang for their kind provision of reagents. We also thank Dr. Alessandro di Maio and Dr. Daniel Gonçalves Carneiro for reading the manuscript and providing rigorous feedback. We further thank Dr. di Maio for their help in the selection of, and training provided for appropriate imaging modalities used throughout this investigation. Finally, thanks are given to Mrs. Rhianne EM Hutchinson-Davies in the generation of diagrammatic cartoons for figures and for final formatting steps. Funding for the work described in this article was provided by a fellowship awarded by the Medical Research Foundation (reference number: MRF-044-0005-F-TRIV-C0824 - SPD), a Juan Rodes fellowship awarded by the European Association for the study of the Liver (2019 award - V.R.), the Sir Jules Thorn Biomedical Charitable Trust (2018 annual award winner; reference number: 18JTA - Y.H.O., N.R. and G.E.W.), a Whitney Wood Scholarship awarded by the Royal College of Physicians, London (2022 award - A.G.B.), and a Transbioline EU grant (N.M.K.).

Keywords

CD8-Positive T-Lymphocytes/immunology
cell invasion
E-cadherin
primary biliary cholangitis
cholangiocytes
cell-in-cell structures
liver

Access to Document

10.1038/s41467-024-44910-2Licence: Creative Commons: Attribution (CC BY)

DaviesS2024ExpressionFinal published version, 20 MBLicence: Creative Commons: Attribution (CC BY)

Cite this

Davies, S. P., Ronca, V., Wootton, G. E., Krajewska, N. M., Bozward, A. G., Fiancette, R., Patten, D. A., Yankouskaya, K., Reynolds, G. M., Pat, S., Osei-Bordom, D. C., Richardson, N., Grover, L. M., Weston, C. J., & Oo, Y. H. (2024). Expression of E-cadherin by CD8⁺ T cells promotes their invasion into biliary epithelial cells. Nature Communications, 15(1), Article 853. https://doi.org/10.1038/s41467-024-44910-2

@article{591afd73646548d9b7f125ff5e38a15c,

title = "Expression of E-cadherin by CD8+ T cells promotes their invasion into biliary epithelial cells",

abstract = "The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been correlated with biliary damage associated with primary biliary cholangitis (PBC). Here, we characterise the mechanism of CD8+ T cell invasion into BEC. CD8+ T cells observed within BEC were large, eccentric, and expressed E-cadherin, CD103 and CD69. They were also not contained within secondary vesicles. Internalisation required cytoskeletal rearrangements which facilitated contact with BEC. Internalised CD8+ T cells were observed in both non-cirrhotic and cirrhotic diseased liver tissues but enriched in PBC patients, both during active disease and at the time of transplantation. E-cadherin expression by CD8+ T cells correlated with frequency of internalisation of these cells into BEC. E-cadherin+ CD8+ T cells formed β-catenin-associated interactions with BEC, were larger than E-cadherin- CD8+ T cells and invaded into BEC more frequently. Overall, we unveil a distinct cell-in-cell structure process in the liver detailing the invasion of E-cadherin+ CD103+ CD69+ CD8+ T cells into BEC.",

keywords = "CD8-Positive T-Lymphocytes/immunology, cell invasion, E-cadherin, primary biliary cholangitis, cholangiocytes, cell-in-cell structures, liver",

author = "Davies, {Scott P.} and Vincenzo Ronca and Wootton, {Grace E.} and Krajewska, {Natalia M.} and Bozward, {Amber G.} and R{\'e}mi Fiancette and Patten, {Daniel A.} and Katharina Yankouskaya and Reynolds, {Gary M.} and Sofia Pat and Osei-Bordom, {Daniel C.} and Naomi Richardson and Grover, {Liam M.} and Weston, {Christopher J.} and Oo, {Ye H.}",

note = "Acknowledgements: The authors are grateful to all patients and donors at the Queen Elizabeth Hospital Birmingham, UK. We would like to thank the whole liver transplantation unit and all the clinical pathology team at the Queen Elizabeth Hospital for sample allocation; and all clinical staff who helped with patient recruitment. Additionally, we would like to thank the NHS team of Daniel Kearns, Janine Fear, Kulvinder Gill and Miriama Havrilova for their continued efforts in managing tissue access at the Centre for Liver and Gastrointestinal Research. We further thank Ms. Havrilova for her time taken to optimise immunohistochemistry stains for our investigation. We also gratefully acknowledge the contribution to this study made by the University of Birmingham{\textquoteright}s Human Biomaterials Resource Centre (HBRC) which has been supported through Birmingham Science City - Experimental Medicine Network of Excellence project. The authors would like to acknowledge the Microscopy Facility at the University of Birmingham for support with confocal microscopy experiments, as well as Birmingham Advanced Light Microscopy facility (BALM) for support with super-resolution and high-content imaging. The authors would also like to acknowledge the University of Birmingham Flow Cytometry Services for assistance with flow cytometry and flow activated cell sorting. All electron microscopy was performed at the Centre for Electron Microscopy, Department of Metallurgy and Materials, University of Birmingham; we gratefully acknowledge their support and assistance in the completion of this project, with particular thanks to Theresa Morris for her help with sample preparation and instrument setup. We give thanks to Bethany Hope James and Dr. Kelly Chiang for their kind provision of reagents. We also thank Dr. Alessandro di Maio and Dr. Daniel Gon{\c c}alves Carneiro for reading the manuscript and providing rigorous feedback. We further thank Dr. di Maio for their help in the selection of, and training provided for appropriate imaging modalities used throughout this investigation. Finally, thanks are given to Mrs. Rhianne EM Hutchinson-Davies in the generation of diagrammatic cartoons for figures and for final formatting steps. Funding for the work described in this article was provided by a fellowship awarded by the Medical Research Foundation (reference number: MRF-044-0005-F-TRIV-C0824 - SPD), a Juan Rodes fellowship awarded by the European Association for the study of the Liver (2019 award - V.R.), the Sir Jules Thorn Biomedical Charitable Trust (2018 annual award winner; reference number: 18JTA - Y.H.O., N.R. and G.E.W.), a Whitney Wood Scholarship awarded by the Royal College of Physicians, London (2022 award - A.G.B.), and a Transbioline EU grant (N.M.K.).",

year = "2024",

month = jan,

day = "29",

doi = "10.1038/s41467-024-44910-2",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Springer",

number = "1",

}

Davies, SP , Ronca, V, Wootton, GE, Krajewska, NM, Bozward, AG, Fiancette, R , Patten, DA, Yankouskaya, K, Reynolds, GM, Pat, S, Osei-Bordom, DC, Richardson, N , Grover, LM , Weston, CJ & Oo, YH 2024, 'Expression of E-cadherin by CD8⁺ T cells promotes their invasion into biliary epithelial cells', Nature Communications, vol. 15, no. 1, 853. https://doi.org/10.1038/s41467-024-44910-2

TY - JOUR

T1 - Expression of E-cadherin by CD8+ T cells promotes their invasion into biliary epithelial cells

AU - Davies, Scott P.

AU - Ronca, Vincenzo

AU - Wootton, Grace E.

AU - Krajewska, Natalia M.

AU - Bozward, Amber G.

AU - Fiancette, Rémi

AU - Patten, Daniel A.

AU - Yankouskaya, Katharina

AU - Reynolds, Gary M.

AU - Pat, Sofia

AU - Osei-Bordom, Daniel C.

AU - Richardson, Naomi

AU - Grover, Liam M.

AU - Weston, Christopher J.

AU - Oo, Ye H.

N1 - Acknowledgements: The authors are grateful to all patients and donors at the Queen Elizabeth Hospital Birmingham, UK. We would like to thank the whole liver transplantation unit and all the clinical pathology team at the Queen Elizabeth Hospital for sample allocation; and all clinical staff who helped with patient recruitment. Additionally, we would like to thank the NHS team of Daniel Kearns, Janine Fear, Kulvinder Gill and Miriama Havrilova for their continued efforts in managing tissue access at the Centre for Liver and Gastrointestinal Research. We further thank Ms. Havrilova for her time taken to optimise immunohistochemistry stains for our investigation. We also gratefully acknowledge the contribution to this study made by the University of Birmingham’s Human Biomaterials Resource Centre (HBRC) which has been supported through Birmingham Science City - Experimental Medicine Network of Excellence project. The authors would like to acknowledge the Microscopy Facility at the University of Birmingham for support with confocal microscopy experiments, as well as Birmingham Advanced Light Microscopy facility (BALM) for support with super-resolution and high-content imaging. The authors would also like to acknowledge the University of Birmingham Flow Cytometry Services for assistance with flow cytometry and flow activated cell sorting. All electron microscopy was performed at the Centre for Electron Microscopy, Department of Metallurgy and Materials, University of Birmingham; we gratefully acknowledge their support and assistance in the completion of this project, with particular thanks to Theresa Morris for her help with sample preparation and instrument setup. We give thanks to Bethany Hope James and Dr. Kelly Chiang for their kind provision of reagents. We also thank Dr. Alessandro di Maio and Dr. Daniel Gonçalves Carneiro for reading the manuscript and providing rigorous feedback. We further thank Dr. di Maio for their help in the selection of, and training provided for appropriate imaging modalities used throughout this investigation. Finally, thanks are given to Mrs. Rhianne EM Hutchinson-Davies in the generation of diagrammatic cartoons for figures and for final formatting steps. Funding for the work described in this article was provided by a fellowship awarded by the Medical Research Foundation (reference number: MRF-044-0005-F-TRIV-C0824 - SPD), a Juan Rodes fellowship awarded by the European Association for the study of the Liver (2019 award - V.R.), the Sir Jules Thorn Biomedical Charitable Trust (2018 annual award winner; reference number: 18JTA - Y.H.O., N.R. and G.E.W.), a Whitney Wood Scholarship awarded by the Royal College of Physicians, London (2022 award - A.G.B.), and a Transbioline EU grant (N.M.K.).

PY - 2024/1/29

Y1 - 2024/1/29

N2 - The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been correlated with biliary damage associated with primary biliary cholangitis (PBC). Here, we characterise the mechanism of CD8+ T cell invasion into BEC. CD8+ T cells observed within BEC were large, eccentric, and expressed E-cadherin, CD103 and CD69. They were also not contained within secondary vesicles. Internalisation required cytoskeletal rearrangements which facilitated contact with BEC. Internalised CD8+ T cells were observed in both non-cirrhotic and cirrhotic diseased liver tissues but enriched in PBC patients, both during active disease and at the time of transplantation. E-cadherin expression by CD8+ T cells correlated with frequency of internalisation of these cells into BEC. E-cadherin+ CD8+ T cells formed β-catenin-associated interactions with BEC, were larger than E-cadherin- CD8+ T cells and invaded into BEC more frequently. Overall, we unveil a distinct cell-in-cell structure process in the liver detailing the invasion of E-cadherin+ CD103+ CD69+ CD8+ T cells into BEC.

AB - The presence of CD8+ T cells in the cytoplasm of biliary epithelial cells (BEC) has been correlated with biliary damage associated with primary biliary cholangitis (PBC). Here, we characterise the mechanism of CD8+ T cell invasion into BEC. CD8+ T cells observed within BEC were large, eccentric, and expressed E-cadherin, CD103 and CD69. They were also not contained within secondary vesicles. Internalisation required cytoskeletal rearrangements which facilitated contact with BEC. Internalised CD8+ T cells were observed in both non-cirrhotic and cirrhotic diseased liver tissues but enriched in PBC patients, both during active disease and at the time of transplantation. E-cadherin expression by CD8+ T cells correlated with frequency of internalisation of these cells into BEC. E-cadherin+ CD8+ T cells formed β-catenin-associated interactions with BEC, were larger than E-cadherin- CD8+ T cells and invaded into BEC more frequently. Overall, we unveil a distinct cell-in-cell structure process in the liver detailing the invasion of E-cadherin+ CD103+ CD69+ CD8+ T cells into BEC.

KW - CD8-Positive T-Lymphocytes/immunology

KW - cell invasion

KW - E-cadherin

KW - primary biliary cholangitis

KW - cholangiocytes

KW - cell-in-cell structures

KW - liver

U2 - 10.1038/s41467-024-44910-2

DO - 10.1038/s41467-024-44910-2

M3 - Article

C2 - 38286990

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 853

ER -