MI2025 – Yang Cheng

Title:
Highly activated intrahepatic HBV-specific resident-memory T and B cells correlated with acute-on-chronic liver failure

Abstract:
Chronic HBV (CHB) patients who have progressive loss of liver function for more than 6 months may lead to chronic liver failure (CLF). In contrast, patients with HBV-associated acute-on-chronic liver failure (ACLF) have dramatic clinical conditions and high short-term mortality due to the sudden loss of substantial amount of hepatocytes, with >80% of the cases lead to death or liver transplantation. However, how the intrahepatic HBV-specific adaptive immunity contribute to the development of two clinically distinct liver diseases is largely unknown. Study of adaptive immune responses in human liver failure is lacking. Here, we recruited patients with HBV-associated ACLF (n=7), HBV-associated CLF (n=3), and HBV-resolved alcohol-induced liver failure (n=1). We probed >100 HBV epitopes and cellular phenotype on patient’s intrahepatic CD8+ T cells, and found that intrahepatic HBV_core– and HBV_polymerase-specific T cells were highly expanded in ACLF patients, together with higher frequencies of liver-infiltrating bystander-specific T cells. Of note, intrahepatic HBV-specific T cells in ACLF patients were significantly enriched for an activated tissue-resident memory T (T_RM) cell phenotype, expressing tissue homing molecules CD69, CD103, and CXCR6. Deep immunoprofiling shows that these cells are proliferating (Ki67+) with cytolytic property (Granzyme B+), and can be further delineated into three activated subsets including CD38^hiHLA-DR^hi, CD38^hiHLA-DR^int, and CD38^intHLA-DR^lo T_RM cells. Importantly, they were not observed in paired blood, or in the liver and blood isolated from CLF and HBV-resolved alcohol-induced liver failure patients. Similarly, intrahepatic HBcAg-, but not HBsAg-specific B cells, were substantially elevated in ACLF patients. The intrahepatic HBcAg-specific B cells obtained an activated atypical memory phenotype expressing IgM. Thus, we provide novel insights of disease-specific adaptive immune responses during the development of HBV-associated ACLF. Our data implies that targeting these cells might have therapeutic potential such as using tolerogenic mRNA vaccine, monoclonal antibody or anti-inflammation drug therapy.

Biography:
Dr. Yang Cheng started his scientific career in immunology by working on T cell immune responses in chronic viral infection and type 1 diabetes using LCMV model in the laboratory of Dr. Matthias von Herrath at the La Jolla Institute for Immunology in San Diego, California. After years of research using murine models, he shifted his research focus to understand human T cell immunity in chronic hepatitis B virus (HBV) infection during his Master’s study under the mentorship of Prof. Mala Maini at University College London. Dr. Cheng completed his Ph.D. and postdoctoral training with Dr. Evan Newell at Singapore Immunology Network (SIgN) of the Agency for Science, Technology and Research (A*STAR), where he spearheaded several research programs using highly multiplexed combinatorial peptide-MHC tetramer strategy and mass cytometry to comprehensively probed peripheral and intrahepatic HBV-specific T cells in patients with chronic HBV infection or hepatocellular carcinoma. His works contributed to the fundamental understanding of T cell exhaustion and memory responses during human chronic HBV infection, and identified novel HBV-specific memory T cells and HBV-reactive T cell receptors (TCR) linked to disease control. Following a short-term appointment as a staff scientist at Massachusetts General Hospital, Dr. Cheng returned to his home country, and joined the Institute of Biomedical Sciences (IBMS) at Academia Sinica as an Assistant Faculty Member in 2023. His research group aims to use various cutting-edge technologies to dissect antigen-specific T cell immunity in great detail in the context of human diseases. The main focus of Cheng Laboratory is to explore the functional relationship of tissue-resident memory T cell and the long-term immune protection against HBV-related diseases and SARS-CoV-2 infection.