Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
PLoS Pathog. 2011 Dec;7(12):e1002389. doi: 10.1371/journal.ppat.1002389. Epub 2011 Dec 1.
Cellular responses to Plasmodium falciparum parasites, in particular interferon-gamma (IFNγ) production, play an important role in anti-malarial immunity. However, clinical immunity to malaria develops slowly amongst naturally exposed populations, the dynamics of cellular responses in relation to exposure are difficult to study and data about the persistence of such responses are controversial. Here we assess the longevity and composition of cellular immune responses following experimental malaria infection in human volunteers. We conducted a longitudinal study of cellular immunological responses to sporozoites (PfSpz) and asexual blood-stage (PfRBC) malaria parasites in naïve human volunteers undergoing single (n = 5) or multiple (n = 10) experimental P. falciparum infections under highly controlled conditions. IFNγ and interleukin-2 (IL-2) responses following in vitro re-stimulation were measured by flow-cytometry prior to, during and more than one year post infection. We show that cellular responses to both PfSpz and PfRBC are induced and remain almost undiminished up to 14 months after even a single malaria episode. Remarkably, not only 'adaptive' but also 'innate' lymphocyte subsets contribute to the increased IFNγ response, including αβT cells, γδT cells and NK cells. Furthermore, results from depletion and autologous recombination experiments of lymphocyte subsets suggest that immunological memory for PfRBC is carried within both the αβT cells and γδT compartments. Indeed, the majority of cytokine producing T lymphocytes express an CD45RO(+) CD62L(-) effector memory (EM) phenotype both early and late post infection. Finally, we demonstrate that malaria infection induces and maintains polyfunctional (IFNγ(+)IL-2(+)) EM responses against both PfRBC and PfSpz, previously found to be associated with protection. These data demonstrate that cellular responses can be readily induced and are long-lived following infection with P. falciparum, with a persisting contribution by not only adaptive but also (semi-)innate lymphocyte subsets. The implications hereof are positive for malaria vaccine development, but focus attention on those factors potentially inhibiting such responses in the field.
疟原虫寄生虫对细胞的反应,特别是干扰素-γ(IFNγ)的产生,在抗疟免疫中起着重要作用。然而,在自然暴露人群中,对疟疾的临床免疫力发展缓慢,与暴露相关的细胞反应的动态难以研究,并且关于此类反应持续存在的数据存在争议。在这里,我们评估了人类志愿者感染实验性疟疾后细胞免疫反应的持久性和组成。我们对在高度受控条件下接受单次(n = 5)或多次(n = 10)实验性疟原虫感染的幼稚人类志愿者对孢子(PfSpz)和无性血期(PfRBC)疟原虫寄生虫的细胞免疫反应进行了纵向研究。在感染前、感染期间和感染后一年以上,通过流式细胞术测量体外再刺激后的 IFNγ 和白细胞介素-2(IL-2)反应。我们表明,即使是单次疟疾发作后,对 PfSpz 和 PfRBC 的细胞反应也被诱导并几乎保持不变,长达 14 个月。值得注意的是,不仅“适应性”,而且“先天”淋巴细胞亚群也有助于增加 IFNγ 反应,包括αβT 细胞、γδT 细胞和 NK 细胞。此外,淋巴细胞亚群的耗竭和自体重组实验的结果表明,PfRBC 的免疫记忆存在于αβT 细胞和γδT 细胞中。事实上,感染后早期和晚期,大多数产生细胞因子的 T 淋巴细胞表达 CD45RO(+) CD62L(-) 效应记忆(EM)表型。最后,我们证明疟原虫感染诱导并维持针对 PfRBC 和 PfSpz 的多效性(IFNγ(+)IL-2(+))EM 反应,先前发现这些反应与保护相关。这些数据表明,在感染疟原虫后,细胞反应可以很容易地被诱导并持续存在,不仅适应性而且(半)先天淋巴细胞亚群也持续发挥作用。这对疟疾疫苗的开发具有积极意义,但需要关注那些可能在现场抑制此类反应的因素。
Parasite Immunol. 1996-7
Elife. 2025-7-23
Signal Transduct Target Ther. 2025-6-17
Front Immunol. 2023-12-6
Expert Rev Vaccines. 2023
Front Immunol. 2022
Vaccines (Basel). 2022-9-14
Front Immunol. 2022
Nat Rev Immunol. 2011-1
Curr Opin Immunol. 2010-4-29