DECAGE · Decoding Immune Aging in Chronic Hepatitis B

Aging is a major global health issue that increases the prevalence of multimorbidity. With the ongoing demographic shift, it is critical to understand how aging heightens susceptibility to chronic disease, disability, and frailty. The immune system is now recognized as a central driver of organismal aging. Dysfunctional adaptive immune cells, particularly T cells, are key accelerators of this process and contribute to multiple age-related pathologies. Age-associated decline in immunity, or immunosenescence, leads to impaired pathogen responses, reduced immune surveillance, and increased risk of autoinflammatory and autoimmune diseases. Thus, understanding immune aging is fundamental to understanding aging as a whole.Prolonged immune activation is a trigger of immune cell dysfunction in cancer and chronic infection. However, the impact of chronic infection on immune aging within non-lymphoid tissues, particularly the liver, remains largely unexplored. This is especially relevant because the liver plays a central role in systemic metabolism, and immune cell metabolism is a critical regulator of immune function. Hepatitis B virus (HBV) induces a unique dysfunctional—yet not exhausted—phenotype in liver-infiltrating CD8⁺ T cells, distinguishing it from other chronic viral infections.This project will integrate chronic HBV infection, aging, and immunometabolism to test the hypothesis that persistent hepatocellular priming drives premature aging of CD8⁺ T cells, but also of CD4+ T cells and B cells. Using high-parameter flow cytometry, multiphoton intravital microscopy, and single-cell RNA sequencing, we will dissect the mechanisms underlying adaptive immune cell dysfunction. Furthermore, we will characterize the role of metabolism in the acquisition of the aging-like phenotype. Finally, access to human samples will enable direct translational validation.