CELLULAR & EXTRACELLULAR ‘CONVERSATIONS’ IN CHRONIC LIVER DISEASE
Lead Research Organisation:
UNIVERSITY COLLEGE LONDON
Abstract
Chronic liver disease (CLD) and its complications affect an estimated 1.5 billion people, accounting for ~2 million deaths each year. Continued insult or injury to the liver of people living with CLD leads to progressive scarring (fibrosis) which subsequently disrupts architecture and function, leading to cirrhosis (advanced fibrosis), liver failure and in some, primary liver cancer. Despite this ever-increasing global healthcare problem therapies for CLD remain limited and largely rely on removal of the ongoing source of injury. Therefore, to move forward and improve clinical prognoses for people with CLD we must discover and develop novel targets with anti-fibrotic potential to reverse fibrosis and ultimately restore liver function.
Within the CLD liver, a highly specialised population of long-lived, resident lymphocytes accumulate. This population of tissue-resident memory T cells (TRM) not only accumulate in CLD but express a range of extracellular matrix (ECM)-binding integrins and adhesion molecules prompting their sequestration with the fibrotic scar. In response to the vast array of environmental cues ranging from the physical and mechanical, to the cellular and metabolic, CLD TRM upregulate programmes of cellular exhaustion, resulting in an altered repertoire of co-inhibitory and co-stimulatory molecules and exhibit a reduced potential for effective antigen-specific immunosurveillance. Similarly, in the CLD liver the underlying hepatic stromal cells – that mediate fibrogenesis - undergo functional specialisation whereby they gain the potential for targeted immunomodulation of TRM effector function via expression of co-inhibitory ligands and the secretion of mediators that limit antigen-specific responses.
However, beyond TRM, it has emerged that other liver-resident lymphocytes, namely B cells can infiltrate and produce profibrotic mediators (e.g. TNF/TGFb) within the organ and thus contribute to liver fibrosis. Therefore, our vision in the second phase of this Fellowship is to extend our current findings to investigate whether the hepatic stroma orchestrate other tissue-compartmentalised lymphocytes in the liver (like B cells) that collaborate with TRM to provide effective host immunosurveillance. More specifically our research objectives will first explore the potential for bidirectional communication between hepatic stromal cells and B cells in CLD investigating the possibility that B cells contribute to fibrogenesis directly in people living with CLD and/or that through the formation of deregulated lymphoid aggregates, underpinned by an altered stromal cell network, B cells also contribute to the reduced antigen-specific effector function by TRM. As part of this we will generate the most detailed ‘immune map’ of the human CLD liver to date, revealing the range and diversity of cellular ‘conversations’ underpinning tissue-resident immunobiology and begin to uncover the potential for stromal cells across different tissues to use common pathways to orchestrate local immunity. We will also investigate other environmental cues dictating TRM biology in health and CLD. For instance, exploring the interaction between TRM and the ECM and the consequence of such interactions, and whether a ‘universal metabolic signature’ for TRM exists or whether a T cells metabolic preference is imprinted by its niche of residence.
Delivery of these objectives will be achieved using a combination of innovative clinical cohorts and existing transcriptomic datasets, state-of-the-art spatial profiling of bio-banked tissue samples and novel single cell metabolic flux analyses. Collectively this continuing research programme will address fundamental questions in T cell biology, liver immunology and the role of liver-resident lymphocytes more broadly in the context of human CLD.
Within the CLD liver, a highly specialised population of long-lived, resident lymphocytes accumulate. This population of tissue-resident memory T cells (TRM) not only accumulate in CLD but express a range of extracellular matrix (ECM)-binding integrins and adhesion molecules prompting their sequestration with the fibrotic scar. In response to the vast array of environmental cues ranging from the physical and mechanical, to the cellular and metabolic, CLD TRM upregulate programmes of cellular exhaustion, resulting in an altered repertoire of co-inhibitory and co-stimulatory molecules and exhibit a reduced potential for effective antigen-specific immunosurveillance. Similarly, in the CLD liver the underlying hepatic stromal cells – that mediate fibrogenesis - undergo functional specialisation whereby they gain the potential for targeted immunomodulation of TRM effector function via expression of co-inhibitory ligands and the secretion of mediators that limit antigen-specific responses.
However, beyond TRM, it has emerged that other liver-resident lymphocytes, namely B cells can infiltrate and produce profibrotic mediators (e.g. TNF/TGFb) within the organ and thus contribute to liver fibrosis. Therefore, our vision in the second phase of this Fellowship is to extend our current findings to investigate whether the hepatic stroma orchestrate other tissue-compartmentalised lymphocytes in the liver (like B cells) that collaborate with TRM to provide effective host immunosurveillance. More specifically our research objectives will first explore the potential for bidirectional communication between hepatic stromal cells and B cells in CLD investigating the possibility that B cells contribute to fibrogenesis directly in people living with CLD and/or that through the formation of deregulated lymphoid aggregates, underpinned by an altered stromal cell network, B cells also contribute to the reduced antigen-specific effector function by TRM. As part of this we will generate the most detailed ‘immune map’ of the human CLD liver to date, revealing the range and diversity of cellular ‘conversations’ underpinning tissue-resident immunobiology and begin to uncover the potential for stromal cells across different tissues to use common pathways to orchestrate local immunity. We will also investigate other environmental cues dictating TRM biology in health and CLD. For instance, exploring the interaction between TRM and the ECM and the consequence of such interactions, and whether a ‘universal metabolic signature’ for TRM exists or whether a T cells metabolic preference is imprinted by its niche of residence.
Delivery of these objectives will be achieved using a combination of innovative clinical cohorts and existing transcriptomic datasets, state-of-the-art spatial profiling of bio-banked tissue samples and novel single cell metabolic flux analyses. Collectively this continuing research programme will address fundamental questions in T cell biology, liver immunology and the role of liver-resident lymphocytes more broadly in the context of human CLD.
People |
ORCID iD |
| Laura Pallett (Principal Investigator / Fellow) |