Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS Pathog. 2011 Sep;7(9):e1002273. doi: 10.1371/journal.ppat.1002273. Epub 2011 Sep 29.
During many chronic infections virus-specific CD8 T cells succumb to exhaustion as they lose their ability to respond to antigenic activation. Combinations of IL-12, IL-18, and IL-21 have been shown to induce the antigen-independent production of interferon (IFN)-γ by effector and memory CD8 T cells. In this study we investigated whether exhausted CD8 T cells are sensitive to activation by these cytokines. We show that effector and memory, but not exhausted, CD8 T cells produce IFN-γ and upregulate CD25 following exposure to certain combinations of IL-12, IL-18, and IL-21. The unresponsiveness of exhausted CD8 T cells is associated with downregulation of the IL-18-receptor-α (IL-18Rα). Although IL-18Rα expression is connected with the ability of memory CD8 T cells to self-renew and efflux rhodamine 123, the IL-18Rα(lo) exhausted cells remained capable of secreting this dye. To further evaluate the consequences of IL-18Rα downregulation, we tracked the fate of IL-18Rα-deficient CD8 T cells in chronically infected mixed bone marrow chimeras and discovered that IL-18Rα affects the initial but not later phases of the response. The antigen-independent responsiveness of exhausted CD8 T cells was also investigated following co-infection with Listeria monocytogenes, which induces the expression of IL-12 and IL-18. Although IL-18Rα(hi) memory cells upregulated CD25 and produced IFN-γ, the IL-18Rα(lo) exhausted cells failed to respond. Collectively, these findings indicate that as exhausted T cells adjust to the chronically infected environment, they lose their susceptibility to antigen-independent activation by cytokines, which compromises their ability to detect bacterial co-infections.
在许多慢性感染中，病毒特异性 CD8 T 细胞由于失去对抗原激活的反应能力而衰竭。已经证明，IL-12、IL-18 和 IL-21 的组合可以诱导效应器和记忆 CD8 T 细胞产生抗原非依赖性的干扰素（IFN）-γ。在这项研究中，我们研究了衰竭的 CD8 T 细胞是否对这些细胞因子的激活敏感。我们表明，效应器和记忆性但非衰竭性 CD8 T 细胞在暴露于某些 IL-12、IL-18 和 IL-21 的组合后会产生 IFN-γ并上调 CD25。衰竭的 CD8 T 细胞的无反应性与 IL-18 受体-α（IL-18Rα）的下调有关。尽管 IL-18Rα 的表达与记忆性 CD8 T 细胞自我更新和排出罗丹明 123 的能力有关，但 IL-18Rα（lo）衰竭细胞仍能够分泌这种染料。为了进一步评估 IL-18Rα 下调的后果，我们在慢性感染的混合骨髓嵌合体中跟踪了缺乏 IL-18Rα 的 CD8 T 细胞的命运，并发现 IL-18Rα 影响反应的初始阶段但不影响后期阶段。在李斯特菌单核细胞增多症（一种诱导 IL-12 和 IL-18 表达的感染）共感染后，我们还研究了衰竭的 CD8 T 细胞的抗原非依赖性反应性。虽然 IL-18Rα（hi）记忆细胞上调 CD25 并产生 IFN-γ，但 IL-18Rα（lo）衰竭细胞没有反应。总的来说，这些发现表明，随着衰竭的 T 细胞适应慢性感染环境，它们失去了对细胞因子的抗原非依赖性激活的敏感性，从而损害了它们检测细菌共感染的能力。
