Hisaeda Hajime, Hamano Shinjiro, Mitoma-Obata Chikage, Tetsutani Kohhei, Imai Takashi, Waldmann Herman, Himeno Kunisuke, Yasutomo Koji
Department of Immunology & Parasitology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Eur J Immunol. 2005 Dec;35(12):3516-24. doi: 10.1002/eji.200526073.
CD4+ T cells are the major effector T cells against blood-stage Plasmodium yoelii infection. On the other hand, the lethal strain of P. yoelii (PyL) has acquired an escape mechanism from host T cell immunity by activating CD4+CD25+ regulatory T cells (Treg). Although the activation of Treg during PyL infection precludes the clearance of PyL from mice, it remains unclear whether activation of Treg is attributable to a specific response against PyL infection. Thus, we examined here whether Treg proliferate in an antigen-dependent manner during PyL infection. We also investigated the effector and regulatory mechanisms of Treg. Infection with PyL increased the number of CD4+CD25+ T cells, in which expression of Foxp3 mRNA is up-regulated. The Treg that were transferred into mice infected with PyL, but not with a non-lethal strain of P. yoelii (PyNL), proliferated during the initial 5 days following infection. The Treg from PyL-infected mice showed strong suppression compared with those from naive or PyNL-infected mice, and could suppress T cell activation by recognizing PyL- but not PyNL-derived antigens. Furthermore, the suppressive function of Treg activated in PyL-infected but not in naive mice could not be inhibited by treatment with an anti-glucocorticoid-induced TNFR family-related protein (GITR) mAb. These findings indicate that PyL infection specifically activates Treg that are specific for PyL-derived antigens. The infection also induces resistance for Treg to GITR signaling, and this eventually contributes to the escape of parasites from host T cell immunity.
CD4+ T细胞是针对血液阶段约氏疟原虫感染的主要效应T细胞。另一方面，约氏疟原虫的致死株（PyL）通过激活CD4+CD25+调节性T细胞（Treg）获得了逃避宿主T细胞免疫的机制。尽管在PyL感染期间Treg的激活阻止了PyL从小鼠体内清除，但Treg的激活是否归因于对PyL感染的特异性反应仍不清楚。因此，我们在此研究了在PyL感染期间Treg是否以抗原依赖性方式增殖。我们还研究了Treg的效应和调节机制。感染PyL会增加CD4+CD25+ T细胞的数量，其中Foxp3 mRNA的表达上调。转入感染PyL而非感染非致死性约氏疟原虫株（PyNL）的小鼠体内的Treg在感染后的最初5天内增殖。与来自未感染或感染PyNL的小鼠的Treg相比，来自感染PyL的小鼠的Treg表现出强烈的抑制作用，并且可以通过识别PyL而非PyNL衍生的抗原来抑制T细胞激活。此外，在感染PyL而非未感染的小鼠中激活的Treg的抑制功能不能被抗糖皮质激素诱导的肿瘤坏死因子受体家族相关蛋白（GITR）单克隆抗体治疗所抑制。这些发现表明，PyL感染特异性激活了对PyL衍生抗原特异的Treg。该感染还诱导Treg对GITR信号产生抗性，这最终导致寄生虫逃避宿主T细胞免疫。
