在持续性抗原刺激下，如慢性感染和癌症中，CD8 T细胞会分化为功能减弱的PD-1阳性（PD-1+）耗竭状态。 耗竭的CD8 T细胞反应由表达转录因子T细胞因子1（TCF-1）和高水平共刺激分子CD28的前体（Tpex）维持。 在这里，我们证明在慢性感染期间维持抗病毒T细胞需要持续的CD28共刺激。 低水平的CD28参与保留了Tpex的线粒体适应能力和自我复制能力，而更强的CD28信号则增强了糖酵解并促进了Tpex分化为TCF-1阴性的耗竭CD8 T细胞（Tex）。 此外，CD28参与增强了分化过程，并不会减少Tpex群体。 这些发现表明，持续的CD28参与对维持PD-1+ CD8 T细胞是必需的，并暗示增加CD28信号有助于Tpex分化为更具功能的效应样Tex，可能不会损害长期反应。

During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.