UNRAVELLING THE CROSSTALK BETWEEN TISSUE-RESIDENT CD4+ T CELLS AND STROMAL CELLS DRIVING LIVER FIBROSIS
Lead Research Organisation:
UNIVERSITY COLLEGE LONDON
Department Name: Infection
Abstract
The liver has an extraordinary capacity to regenerate, yet chronic insult can lead to uncontrolled tissue repair, scarring (fibrosis) and ultimately organ failure. Profibrogenic mediators that accumulate upon injury activate resident stromal cells to differentiate into myofibroblasts aberrantly secreting extracellular matrix (ECM) ? these myofibroblasts aThe liver has an extraordinary capacity to regenerate, yet chronic insult can lead to uncontrolled tissue repair, scarring (fibrosis) and ultimately organ failure. Pro-fibrogenic mediators that accumulate upon injury activate resident stromal cells to differentiate into myofibroblasts aberrantly secrete extracellular matrix (ECM) - these myofibroblasts are the 'master mediators' of fibrosis. The ability of specialised T cells that reside permanently in tissues, tissue resident T cells (TRM), to provide efficient local immunity has ignited interest in harnessing their power for immunotherapy, however emerging data suggest they may interact with stromal cells, and may contribute to tissue damage. The interplay between hepatic TRM and stromal cells, in health and disease, remains unknown. Therefore, I hypothesise that TRM interact and communicate with stromal cells to cross-regulate cell distribution, survival, function and fibrogenic potential to exacerbate (or limit) liver disease.
Moreover, I propose that the retention of 'poised' T cells and their in-situ localisation is influence by bidirectional signalling with the underlying stromal cells. In addition, as fibrosis progresses, I propose the function of TRM becomes dysregulated favouring the production of pro-fibrogenic mediators, that in turn enhance myofibroblast differentiation.
Collectively, by understanding the cellular crosstalk between ECM-producing stromal cells and TRM in the liver this research aims to reveal new anti-fibrotic approaches for clinical translation to promote fibrosis regression and limit ECM deposition - an urgent unmet clinical need.
Moreover, I propose that the retention of 'poised' T cells and their in-situ localisation is influence by bidirectional signalling with the underlying stromal cells. In addition, as fibrosis progresses, I propose the function of TRM becomes dysregulated favouring the production of pro-fibrogenic mediators, that in turn enhance myofibroblast differentiation.
Collectively, by understanding the cellular crosstalk between ECM-producing stromal cells and TRM in the liver this research aims to reveal new anti-fibrotic approaches for clinical translation to promote fibrosis regression and limit ECM deposition - an urgent unmet clinical need.
Organisations
- UNIVERSITY COLLEGE LONDON (Lead Research Organisation)
- Queen Mary University of London (Collaboration)
- Francis Crick Institute (Collaboration)
- Hannover Medical School (Collaboration)
- University College London (Collaboration)
- UNIVERSITY OF EDINBURGH (Collaboration)
- UNIVERSITY OF MANCHESTER (Collaboration)
Publications
Pallett LJ
(2023)
Tissue CD14+CD8+ T cells reprogrammed by myeloid cells and modulated by LPS.
in Nature
| Description | Career Enhancing Grant (GF) |
| Amount | £3,040 (GBP) |
| Organisation | British Society For Immunology |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2024 |
| End | 01/2025 |
| Description | Acquisition of clinical samples: QMUL |
| Organisation | Queen Mary University of London |
| Department | Blizard Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Immunology experience T cell biology |
| Collaborator Contribution | As a lab we are interested in profiling resident T cells in the context of chronic liver disease. Through our in-house sample routes we do not have access to clinical biopsies taken from individuals living with fatty liver disease, unless they reach the point surgery is required. Our consultant collaborators at QMUL do regular biopsies of patients for clinical diagnostics. This collaboration allows us to access material deemed surplus to diagnostic requirements for us to investigate using our experimental pipelines. |
| Impact | ongoing |
| Start Year | 2022 |
| Description | Establishing novel 3D models for the study of CLD (Rombouts; UCL ILDH) |
| Organisation | University College London |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Knowledge exchange Experimental set up, data interpretation Protocol sharing |
| Collaborator Contribution | Knowledge exchange Experimental set up, data interpretation Protocol sharing |
| Impact | no outcomes yet |
| Start Year | 2024 |
| Description | Interrogating B cell phenotypes and B cell-fibroblast crosstalk in fibrosis (UoM) |
| Organisation | University of Manchester |
| Department | Manchester Museum |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Sharing of protocols, Knowledge exchange |
| Collaborator Contribution | Experimental validation in liver tissue (Hyperion profiling on our behalf) Knowledge exchange Sharing of protocols |
| Impact | not outcomes yet |
| Start Year | 2025 |
| Description | Investigating T cell heterogeneity in the human liver: University of Edinburgh |
| Organisation | University of Edinburgh |
| Department | Medical School Edinburgh |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | T cell heterogeneity in human tissues is vast. We have extensive expertise profiling T cells within the liver, but this to date, has relied on a biased selection of markers for flow cytometric analysis. With the rise of single cell transcriptomics/single cell proteomics and spatial transcriptomics we now have a way to assess T cell heterogeneity in an unbiased manner. The Ramachandran lab (University of Edinburgh) are experts in the transcriptomic analysis of the human fibrotic liver with an interest in macrophage heterogeneity. My postdoc will be visiting the Ramachandran lab for an extended period of time (funded by a BSI Career Enhancing Award) to undertake the T cell work using their platforms/pipelines/computational algorithms. |
| Collaborator Contribution | The Ramachandran lab already has a well-characterised portfolio of data at the single-cell level that will allow for the preliminary assessment of T cell heterogenity in the liver. Together, we will be reanalysing these data with our T cell knowledge. Beyond the analysis of existing data, my postdoc, will be undertaking some spatial transcriptomic analysis in the Ramachandran lab to further our understanding. The Ramachandran lab will be providing the equipmental, experimental know-how and support for data analysis/data interpretation. |
| Impact | ongoing BSI Career Enhancing Award to my postdoc |
| Start Year | 2023 |
| Description | Profiling CD14-expressing T cells in ascites: Hannover Medical School |
| Organisation | Hannover Medical School |
| Department | Institute of Immunology |
| Country | Germany |
| Sector | Academic/University |
| PI Contribution | The partnership between Hannover Medical School (HMS) and UCL seeks to further our understanding of resident T cells that have undergone a 're-education' upon interaction with local myeloid cells - this work directly follows on from our recently published work in Nature - Pallett L.J. et al, Nature 2023. We are providing the expertise and experience required to undertake a phenotypic and functional assessment of CD14+ CD8 T cells in the ascitic fluid. We are also providing experimental reagents, laboratory space and machine time for a visiting researcher from HMS (funded by an EMBO visiting scientist award) |
| Collaborator Contribution | Hannover Medical School (HMS) approached us to enter an academic research collaboration to investigate the phenotypic and functional profile of CD14-expressing T cells in samples taken from clinics in Germany. In our original study we highlighted the role for these cells in ascites with some preliminary data. HMS have an extensive well-characterised cohort of samples (and the clinical know-how) to continue our investigation into these unique cells. HMS have also provided a visiting researcher to spend ~5-6 months in my laboratory. |
| Impact | EMBO visiting scientist award |
| Start Year | 2023 |
| Description | Profiling patterns of ECM in the healthy & fibrotic liver: CRICK |
| Organisation | Francis Crick Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | As part of our ongoing work to understand how resident T cells are retained in the human liver we are interested in whether the local ECM and its associated matrisome can dictate the in situ localisation of intrahepatic T cells. We are experts in processing tissues for single cell analysis, but have limited ability to determine the native architecture of the human liver ECM. We therefore, together with the Sahai lab, will use our clinical samples and knowledge of the T cell compartment, to assess the ECM landscape and how this relates to T cell retention. In kind, we offer immunology expertise to the Sahai lab. |
| Collaborator Contribution | The Sahai lab at the CRICK have expertise pertaining to the assessment of the patterns of ECM laid down in tissues in the context of cancer. Together, as part of an ongoing research collaboration, we will be seeking to use the experimental pipelines and computational algorithms to assess the ECM landscape in the fibrotic human liver. Members of the Sahai lab will provide experimental reagents, expertise, and support for this work. |
| Impact | ongoing |
| Start Year | 2021 |