Progenitor and Terminal Subsets of CD8 ⁺ T Cells Cooperate to Contain Chronic Viral Infection

Chronic infections strain the regenerative capacity of antiviral T lymphocyte populations, leading to failure in long-term immunity. The cellular and molecular events controlling this regenerative capacity, however, are unknown. We found that two distinct states of virus-specific CD8(+) T cells exist in chronically infected mice and humans. Differential expression of the T-box transcription factors T-bet and Eomesodermin (Eomes) facilitated the cooperative maintenance of the pool of antiviral CD8(+) T cells during chronic viral infection. T-bet(hi) cells displayed low intrinsic turnover but proliferated in response to persisting antigen, giving rise to Eomes(hi) terminal progeny. Genetic elimination of either subset resulted in failure to control chronic infection, which suggests that an imbalance in differentiation and renewal could underlie the collapse of immunity in humans with chronic infections.