Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC 20037, USA.
J Immunol. 2011 Nov 1;187(9):4421-5. doi: 10.4049/jimmunol.1102319. Epub 2011 Sep 26.
CD8 exhaustion mediated by an inhibitory programmed death-1-programmed death ligand-1 (PD-L1) pathway occurs in several chronic infections, including toxoplasmosis. Although blockade of the programmed death-1-PD-L1 pathway revives this response, the role of costimulatory receptors involved in this rescue has not been ascertained in any model of CD8 exhaustion. This report demonstrates that one such costimulatory pathway, CD40-CD40L, plays a critical role during rescue of exhausted CD8 T cells. Blockade of this pathway abrogates the ameliorative effects of anti-PD-L1 treatment on CD8 T cells. Additionally, we demonstrate in an infectious disease model that CD8-intrinsic CD40 signaling is important for optimal CD8 polyfunctionality, proliferation, T-bet upregulation, and IL-21 signaling, albeit in the context of CD8 rescue. The critical role of CD40 during the rescue of exhausted CD8 T cells may provide a rational basis for designing novel therapeutic vaccination approaches.
CD8 耗竭是由抑制性程序性死亡受体 1-程序性死亡配体 1（PD-L1）途径介导的，发生于多种慢性感染，包括弓形虫病。虽然阻断程序性死亡受体 1-PD-L1 途径可以恢复这种反应，但在 CD8 耗竭的任何模型中，参与这种挽救的共刺激受体的作用尚未确定。本报告表明，共刺激途径 CD40-CD40L 在耗竭的 CD8 T 细胞的挽救中发挥关键作用。阻断该途径可消除抗 PD-L1 治疗对 CD8 T 细胞的改善作用。此外，我们在传染病模型中证明，CD8 内在的 CD40 信号对于最佳的 CD8 多功能性、增殖、T 细胞转录因子的上调和 IL-21 信号至关重要，尽管是在 CD8 挽救的背景下。CD40 在耗竭的 CD8 T 细胞挽救中的关键作用可能为设计新型治疗性疫苗接种方法提供合理的依据。
