The role of mucosal-associated invariant T cells in children with autoimmune liver disease

Warner, Suzan Shou Ying (2023). The role of mucosal-associated invariant T cells in children with autoimmune liver disease. University of Birmingham. Ph.D.

Preview

Warner2023PhD.pdf
Text - Accepted Version
Available under License All rights reserved.
Download (8MB) | Preview

Abstract

Mucosal-associated invariant T (MAIT) cells, defined as CD3+ Valpha7.2+ CD161++ T lymphocytes, are central in the immunosurveillance and maintenance of mucosal integrity. Transcriptomic studies has revealed a tissue repair signature and in health, MAIT cells adopts a regenerative role, releasing antifibrotic cytokines like interleukin-22 at steady state. In chronic liver disease, intrahepatic MAIT cells predominantly localizes to the fibrotic septae and peribiliary regions, most notably in Primary sclerosing cholangitis (PSC). Autoimmune liver disease (AILD), including PSC, are lifelong chronic immune-mediated hepato- biliary disorders that often presents in childhood. There is no cure except for liver transplantation (LT) and even then, the recurrence rate is high. In adult AILD, intrahepatic MAIT cells displays an activation-induced cell exhaustion state with functional IFNγ and TNF impairment. Furthermore, polarization to the profibrotic MAIT17 phenotype occurs with chronic stimulation. MAIT cells are therefore speculated to augment biliary epithelial damage and disease progression in AILD. This project examines the biological characterization of MAIT cells and their functional activity in children with AILD which has not been investigated. Deciphering the early immunopathogenesis of this lifetime condition may provide pathways to explore new treatment options in the future for this debilitating disease. In this research, intrahepatic MAIT cells were confirmed in paediatric liver explants and in terms of function, MAIT cells from children with PSC had preserved TNF secretion in association with upregulated TNF superfamily activity. These PSC MAIT cells also displayed an early polarization towards the chronic inflammatory MAIT17 phenotype. Findings from my research signify that MAIT cells play an important role in the pathogenesis of paediatric autoimmune liver disease. Deciphering this early immunopathogenesis may provide pathways to explore new treatment options for this debilitating lifelong disease.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):