New findings: epigenetic scarring of exhausted T cells in chronic viral infection

In this recent study published in Nature Immunology, researchers found exhausted T cells retained epigenetic ‘scars’ restraining their optimal recovery even after cure of chronic infection.

Long-term exposure to cancer and chronic viral infections can lead to the exhaustion of immune system fighting cells called T lymphocytes. These exhausted T cells have a reduced immune response and are less able to kill virus-infected cells or tumor cells. We now know that these exhausted T cells have a unique phenotypic, functional, transcriptional and epigenetic make-up that differentiates them from other T cells. However, it’s unclear whether this unique make-up in exhausted T cells changes once chronic exposure to viral infection or tumours has ceased.

In this study, Abdel-Hakeem et al. at the Perelman School of Medicine, University of Pennsylvania, used a mouse model of T cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to look at the phenotypic, functional, transcriptional and epigenetic changes in the exhausted T cells upon removal from chronic viral exposure.

Study results showed that only a fraction of exhausted T cells survived after the removal of chronic viral infection. Those surviving T cells acquired some phenotypic and transcriptional features of memory-type T cells which help sustain a long-term immune defense following acute infection or vaccination. Despite these memory-like features, these exhausted T cells underwent only minor changes in their chromatin accessibility profile. Thus, these T cells retained an epigenetic identity that maintained their ineffective state of exhaustion, especially when challenged with the virus again.

These findings suggest that exhausted T cells have permanent epigenetic ‘scarring’ that compromises their ability to provide an adequate immune response. This has implications for the development of targeted therapies able to reverse this epigenetic state. Such therapies could have the potential to enhance the quality and durability of immune responses of previously exhausted T cells for the treatment of cancer relapse and to improve immunity following cure of chronic viral infection.

Reference: Abdel-Hakeem, M.S.*, Manne, S., Beltra, JC. et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat Immunol 22, 1008–1019 (2021).

*Mohamed Abdel-Hakeem received a CanHepC post-doctoral trainee fellowship.

Photo credit: Image by Arek Socha from Pixabay