Prolonged antigen presentation is required for optimal CD8+ T cell responses against malaria liver stage parasites.
Prolonged antigen presentation is required for optimal CD8+ T cell responses against malaria liver stage parasites.
复制标题
DOI：
10.1371/journal.ppat.1000877
复制
发表时间：
2010-05-06
期刊：
影响因子：
6.7
通讯作者：
Zavala F
中科院分区：
文献类型：
--
作者：
Cockburn IA;Chen YC;Overstreet MG;Lees JR;van Rooijen N;Farber DL;Zavala F
用辐照的子孢子进行免疫接种是目前针对疟疾寄生虫的肝脏阶段的最有效的疫苗接种策略，但支持这种方法成功的机制尚不清楚。在这里，我们表明，保护性CD 8 + T细胞反应的完整发展需要延长的抗原呈递。使用特异于疟疾环子孢子蛋白（一种主要的疫苗候选物）的TCR转基因细胞，我们发现子孢子抗原在免疫后持续超过8周，这是一个显著的发现，因为照射后的子孢子不能复制，并且不能分化超过早期肝脏阶段。在淋巴器官中检测到持续抗原，并取决于CD 11 c+细胞的存在。延长的抗原呈递以多种方式增强了CD 8 + T细胞应答的幅度。首先，减少致敏的CD 8 + T细胞在体内暴露于抗原的时间严重减少了发育记忆群体的最终大小。第二，完全发育的记忆细胞在先前免疫的小鼠中扩增，但在转移到幼稚动物中时却没有扩增。最后，持续存在的抗原能够引发幼稚细胞，包括最近的胸腺移民，成为能够消除肝脏中寄生虫的功能性效应细胞。总之，这些数据表明，针对疟疾肝脏阶段的保护性CD 8 + T细胞免疫的最佳发展依赖于子孢子衍生抗原的延长呈递。疟疾每年造成50万至20万人死亡，主要是在非洲。可能需要一种安全有效的疫苗来控制或根除这种疾病。研究表明，如果人们被经过辐射处理的感染疟疾的蚊子叮咬，他们可以免受完全传染性的叮咬。辐射使蚊子体内的寄生虫（称为子孢子）无法分裂;然而，受辐射的寄生虫仍然能够刺激免疫系统，以提供对完全传染性寄生虫的保护。许多试验疫苗是基于试图以安全且具有成本效益的方式模拟辐照子孢子诱导的免疫应答。我们想知道子孢子如何能够有效地诱导免疫反应。我们发现孢子体分子在免疫后被免疫系统保留数月。这些分子继续刺激免疫系统的细胞，使它们分裂更多，从而可能更好地保护。免疫系统在寄生虫本身消失后很长时间内保留寄生虫物质的能力是显着的，并为疫苗如何产生有效的免疫反应提供了新的见解。
Immunization with irradiated sporozoites is currently the most effective vaccination strategy against liver stages of malaria parasites, yet the mechanisms underpinning the success of this approach are unknown. Here we show that the complete development of protective CD8+ T cell responses requires prolonged antigen presentation. Using TCR transgenic cells specific for the malaria circumsporozoite protein, a leading vaccine candidate, we found that sporozoite antigen persists for over 8 weeks after immunization—a remarkable finding since irradiated sporozoites are incapable of replication and do not differentiate beyond early liver stages. Persisting antigen was detected in lymphoid organs and depends on the presence of CD11c+ cells. Prolonged antigen presentation enhanced the magnitude of the CD8+ T cell response in a number of ways. Firstly, reducing the time primed CD8+ T cells were exposed to antigen in vivo severely reduced the final size of the developing memory population. Secondly, fully developed memory cells expanded in previously immunized mice but not when transferred to naïve animals. Finally, persisting antigen was able to prime naïve cells, including recent thymic emigrants, to become functional effector cells capable of eliminating parasites in the liver. Together these data show that the optimal development of protective CD8+ T cell immunity against malaria liver stages is dependent upon the prolonged presentation of sporozoite-derived antigen. Malaria causes the deaths of 0.5–2 million people each year, mainly in Africa. A safe and effective vaccine is likely needed for the control or eradication of this disease. It has been shown that if people are bitten by malaria-infected mosquitoes that have been irradiated they are protected against fully infectious bites. Radiation makes the parasites in the mosquito (called sporozoites) incapable of dividing; however, the irradiated parasites are still capable of stimulating the immune system to provide protection against fully infectious parasites. Many trial vaccines are based on trying to simulate the immune response induced by irradiated sporozoites in a safe and cost-effective way. We want to know how sporozoites are able to efficiently induce immune responses. We found that sprozoite molecules are retained by the immune system for months after immunization. These molecules continue to stimulate the cells of the immune system such that they divide more and thus probably protect better. The ability of the immune system to retain parasite material long after the parasites themselves have disappeared is remarkable and gives new insights into how effective immune responses can be generated by vaccines.
登录
查看更多内容
影响因子：
4.4
作者：
CHEN, JZ;TROUNSTINE, M;HUSZAR, D
通讯作者：
HUSZAR, D
影响因子：
32.4
作者：
Jung, S;Unutmaz, D;Lang, RA
通讯作者：
Lang, RA
影响因子：
4.4
作者：
Jelley-Gibbs, Dawn M.;Dibble, John P.;Swain, Susan L.
通讯作者：
Swain, Susan L.
DOI：
10.4269/ajtmh.1975.24.397
发表时间：
1975-01-01
影响因子：
3.3
作者：
CLYDE, DF;MCCARTHY, VC;WOODWARD, WE
通讯作者：
WOODWARD, WE
影响因子：
4.4
作者：
Asselin-Paturel, C;Brizard, G;Trinchieri, G
通讯作者：
Trinchieri, G