T cells play an important role in the clearance of hepatotropic viruses but may also cause liver injury and contribute to disease progression in chronic hepatitis B and C virus infections which affect millions of people worldwide. The liver provides a unique microenvironment of immunological tolerance and hepatic immune regulation can modulate the functional properties of T cell subsets and influence the outcome of a virus infection. Extensive research over the last years has advanced our understanding of hepatic conventional CD4+ and CD8+ T cells and unconventional T cell subsets and their functions in the liver environment during acute and chronic viral infections. The recent development of new small animal models and technological advances should further increase our knowledge of hepatic immunological mechanisms. Here we provide an overview of the existing models to study hepatic T cells and review the current knowledge about the distinct roles of heterogeneous T cell populations during acute and chronic viral hepatitis.

After birth, the immune system must learn to tolerate a rapidly changing milieu of commensals and self while remaining ready for pathogens. Here we characterize the neonatal liver as a central hub in this process: In postnatal week 1–2, the liver hosts a developmentally encoded, microbiota-independent expansion of regulatory T cells (Tregs) that coexists with microbiota-tuned conventional wave of activated CD4⁺ T cells (Tconvs). Mechanistically, the Treg expansion is governed by MHCII-mediated antigen presentation by CCR7+ cDC1s, which establish tolerogenic DC:T cell clusters in the liver parenchyma, allowing for local expansion and control via PD-L1 checkpoints that selectively increase Tregs without unleashing Tconvs. Importantly, this transient, neonatal program predisposes hepatotropic viral infections to progress toward chronic disease but also protects the adult liver from steatotic disease. These data position the neonatal liver as a unique site of early life T-cell education with timing-sensitive implications for early-life interventions.