CD8+ T cell exhaustion has been thought to occur only in the context of chronic antigen persistence, such as in cancer or chronic viral infections. However, two papers now published in Nature show that these cells and their precursors are present in the early stages of an acute infection with lymphocytic choriomeningitis virus in mice. In one of the studies, they also detected virus-specific stem-like precursors of exhausted T (Tpex) cells in the early pre-chronic stage of a viral infection that would go on to become chronic. Using methods such as fate mapping and adoptive transfer, the authors found that these cells could adapt to their environment by either maintaining a stem-like phenotype during chronic antigen exposure or switching to (or outgrowth of) a central memory-like T cell in acute infections. The maintenance of Tpex cells in acute infections seems to be mediated by high-affinity T cell receptor ligation, rather than by chronic antigen exposure. Together, these papers support the idea that T cell exhaustion is not a dysfunctional state in viral infection, but a highly regulated program poised to counter different viruses and infection conditions.

Original references: Nature https://doi.org/10.1038/s41586-024-08451-4 (2025); Nature https://doi.org/10.1038/s41586-024-08562-y (2025)