Department of Microbiology, Kyoto University Graduate School of Medicine, Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
Int Immunol. 2010 Dec;22(12):915-25. doi: 10.1093/intimm/dxq446. Epub 2010 Nov 3.
A major concern still prevails as to the reason why various mycobacteria are able to persist within infected host in which protective immunity is generated. To address this question, we monitored the generation of protective T cells during infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG). CD4(+) T cells obtained 3 weeks after infection conferred protection against Mycobacterium tuberculosis challenge and produced IFN-γ and tumor necrosis factor (TNF)-α upon antigen stimulation. However, these abilities were decreased after 6 weeks of infection even though BCG was not thoroughly eliminated from the host. We analyzed the expression of ligands for the CD28/CTLA-4 family receptors on antigen-presenting cells and found that the expression of PD-L1, a ligand for programmed cell death-1 (PD-1), was up-regulated later than 3 weeks of infection. We also found that bacterial numbers in the spleen of PD-1-deficient mice were significantly reduced compared with wild-type mice at 6 and 12 weeks after BCG infection. Furthermore, CD4(+) T cells of PD-1-deficient mice showed a higher ability to confer protection and produce IFN-γ and TNF-α even at 12 weeks after infection. These results indicate that the PD-1-PD-L1 pathway impairs T(h)1 immunity in the late stage of BCG infection, thereby facilitating the bacterial persistence in the host.
目前仍存在一个主要问题，即为什么各种分枝杆菌能够在宿主中持续存在，而宿主已经产生了保护性免疫。为了解决这个问题，我们监测了感染牛分枝杆菌卡介苗（BCG）期间保护性 T 细胞的产生。感染后 3 周获得的 CD4(+)T 细胞能够抵御结核分枝杆菌的攻击，并在抗原刺激下产生 IFN-γ 和肿瘤坏死因子 (TNF)-α。然而，尽管 BCG 并未从宿主中彻底清除，但在感染 6 周后，这些能力下降了。我们分析了抗原呈递细胞上 CD28/CTLA-4 家族受体配体的表达情况，发现程序性死亡蛋白-1（PD-1）配体 PD-L1 的表达在感染后 3 周后上调。我们还发现，与野生型小鼠相比，PD-1 缺陷型小鼠在 BCG 感染后 6 和 12 周时脾脏中的细菌数量明显减少。此外，PD-1 缺陷型小鼠的 CD4(+)T 细胞即使在感染 12 周后，也具有更高的保护能力，并能产生 IFN-γ 和 TNF-α。这些结果表明，PD-1-PD-L1 途径在 BCG 感染后期损害了 Th1 免疫，从而促进了细菌在宿主中的持续存在。
