In the mid-1990s, I was a clinical PhD student attending my first international immunology conference in San Francisco, where I heard a paper presented by Frank Chisari that revolutionized the existing dogma of cytotoxic T lymphocytes (CTLs). The findings published by Luca Guidotti et al. in 1996 provided definitive evidence in a transgenic mouse model of hepatitis B virus (HBV) infection that CD8+ T cells could exert potent antiviral efficacy without lysing infected cells.

They showed that small numbers of HBV-specific CD8+ T cells could clear the virus from infected hepatocytes throughout the liver in a perforin-independent manner. This non-cytolytic ‘cure’ was mediated by the production of IFNγ and tumour necrosis factor by CD8+ T cells, which allowed for amplification of the effect over a longer range and for preservation of tissue integrity. Thus, small numbers of specific T cells had the potential to cure a widespread hepatotropic viral infection without destroying this vital organ.

This discovery provided a strong rational to support subsequent efforts to harness CD8+ T cells for immunotherapy of infections such as HBV, with the aim of achieving immunological cure with minimal damage to the infected liver. The paradigm of CD8+ T cells mediating their effector function through soluble mediators, in addition to lysis, turned out to be relevant in many settings beyond HBV. This realization that CTLs were not necessarily cytotoxic led to widespread use of the more generic term ‘CD8+ T cells’ and to the adoption of functional assays based on their cytokine production.

Returning to the lab inspired by the conference, I scrutinized the literature and decided to direct my future research into HBV immunology, which linked well with my clinical specialization. Looking into what could be done in the human system, I came across work by Antonio Bertoletti and Carlo Ferrari defining HLA-A2-restricted HBV epitopes and showing that naturally occurring viral variants could antagonize cognate CD8+ T cells. I was excited by the exquisite precision of virus-specific CD8+ T cells but frustrated by the laborious techniques required to detect them at that time. However, peptide–MHC tetramers had just been described by John Altman et al. for the direct ex vivo analysis of antigen-specific CD8+ T cells, so I contacted Andrew McMichael and persuaded his lab to construct one for an HBV epitope that Antonio Bertoletti had defined. Imagine my delight when I then discovered that Antonio was about to move to UCL, where I worked — it was the start of a great collaboration and I’ve focused on HBV immunology ever since.