Malaria vaccines, comprised of irradiated Plasmodium falciparum sporozoites or a synthetic peptide containing T and B cell epitopes of the circumsporozoite protein (CSP), elicit multifunctional cytotoxic and non-cytotoxic CD4(+) T cells in immunised volunteers. Both lytic and non-lytic CD4(+)T cell clones recognised a series of overlapping epitopes within a 'universal' T cell epitope EYLNKIQNSLSTEWSPCSVT of CSP (NF54 isolate) that was presented in the context of multiple DR molecules. Lytic activity directly correlated with T cell receptor (TCR) functional avidity as measured by stimulation indices and recognition of naturally occurring variant peptides. CD4(+) T cell-mediated cytotoxicity was contact-dependent and did not require de novo synthesis of cytotoxic mediators, suggesting a granule-mediated mechanism. Live cell imaging of the interaction of effector and target cells demonstrated that CD4(+) cytotoxic T cells recognise target cells with their leading edge, reorient their cytotoxic granules towards the zone of contact, and form a stable immunological synapse. CTL attacks induced chromatin condensation, nuclear fragmentation and formation of apoptotic bodies in target cells. Together, these findings suggest that CD4(+) CTLs trigger target cell apoptosis via classical perforin/granzyme-mediated cytotoxicity, similar to CD8(+) CTLs, and these multifunctional sporozoite- and peptide-induced CD4(+) T cells have the potential to play a direct role as effector cells in targeting the exoerythrocytic forms within the liver.

中文翻译：

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对恶性疟原虫环子孢子蛋白特异的人细胞毒性 CD4+ T 细胞的成像效应子功能。

疟疾疫苗由辐照的恶性疟原虫子孢子或含有环子孢子蛋白 (CSP) 的 T 和 B 细胞表位的合成肽组成，在免疫志愿者中引发多功能细胞毒性和非细胞毒性 CD4(+) T 细胞。裂解和非裂解 CD4(+)T 细胞克隆均识别出 CSP（NF54 分离物）的“通用”T 细胞表位 EYLNKIQNSLSTEWSPCSVT 内的一系列重叠表位，该表位出现在多个 DR 分子的背景下。溶解活性与 T 细胞受体 (TCR) 功能亲合力直接相关，如通过刺激指数和对天然变异肽的识别来衡量的。CD4(+) T 细胞介导的细胞毒性是依赖于接触的，不需要细胞毒性介质的从头合成，表明是颗粒介导的机制。效应细胞和靶细胞相互作用的活细胞成像表明，CD4(+) 细胞毒性 T 细胞通过其前沿识别靶细胞，将其细胞毒性颗粒重新定向到接触区，并形成稳定的免疫突触。CTL 攻击在靶细胞中诱导染色质凝聚、核碎裂和凋亡小体的形成。总之，这些发现表明 CD4(+) CTL 通过经典的穿孔素/颗粒酶介导的细胞毒性触发靶细胞凋亡，类似于 CD8(+) CTL，并且这些多功能子孢子和肽诱导的 CD4(+) T 细胞具有潜力作为效应细胞在靶向肝脏内的红细胞外形式方面发挥直接作用。将它们的细胞毒性颗粒重新定向到接触区，并形成稳定的免疫突触。CTL 攻击在靶细胞中诱导染色质凝聚、核碎裂和凋亡小体的形成。总之，这些发现表明 CD4(+) CTL 通过经典的穿孔素/颗粒酶介导的细胞毒性触发靶细胞凋亡，类似于 CD8(+) CTL，并且这些多功能子孢子和肽诱导的 CD4(+) T 细胞具有潜力作为效应细胞在靶向肝脏内的红细胞外形式方面发挥直接作用。将它们的细胞毒性颗粒重新定向到接触区，并形成稳定的免疫突触。CTL 攻击在靶细胞中诱导染色质凝聚、核碎裂和凋亡小体的形成。总之，这些发现表明 CD4(+) CTL 通过经典的穿孔素/颗粒酶介导的细胞毒性触发靶细胞凋亡，类似于 CD8(+) CTL，并且这些多功能子孢子和肽诱导的 CD4(+) T 细胞具有潜力作为效应细胞在靶向肝脏内的红细胞外形式方面发挥直接作用。