Bergmann E S, Ballou R W, Krzych U
Department of Immunology, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Cell Immunol. 1997 Sep 15;180(2):143-52. doi: 10.1006/cimm.1997.1186.
Malaria is caused by Plasmodium spp. and is one of the major infectious diseases leading to morbidity and mortality in tropical areas of the world. The model of protective immunity induced by immunization with radiation-attenuated Plasmodia sporozoites (SPZ) has become the framework for the elucidation of protective immune mechanisms and the prototype for a promising vaccine strategy. We have previously reported that although considered stage specific based on antibody and CD8+ cytolytic T lymphocyte responses directed against preerythrocytic stage antigens, in particular, the circumsporozoite protein and sporozoite surface protein 2, protective immunity induced in humans by attenuated Plasmodium falciparum SPZ may also involve CD4+ T cell responding to antigens present on parasitized red blood cells (pRBC). In this study we examined the functional role of pRBC responding CD4+ T cells by comparing in vitro pRBC-stimulated responses of CD4+ T cells from persons during preimmunity to irradiated SPZ, during induction of protection, and infection induced with SPZ. The results reported herein corroborate previously published observations that antigens associated with pRBC induce proliferative CD4+ lymphocytes responses in subjects exposed to malaria parasite-derived antigens and not malaria-naive persons; however, now we demonstrate that pRBC-proliferative CD4+ T cells did not coincide with protective immunity. Similarly, pRBC-induced IFN-gamma levels did not distinguish malaria protected from susceptible persons, although IFN-gamma was observed only in lymphocyte cultures from malaria parasite-exposed volunteers and not in lymphocyte cultures from malaria-naive persons. In contrast, we noted an increase in the IL-4-producing CD4+ T cells that also exhibited the memory phenotype, CD45RO, and an upregulated expression of CD25 in cultures from malaria protected persons as compared to malaria naive persons and subjects who became parasitemic. Hence, these observations suggest that the induction of memory CD4+ T cell subset distinguished by the expression of CD45RO and CD25 and production of IL-4 coincides with protective immune responses generated by immunization with attenuated SPZ.
疟疾由疟原虫属引起，是导致世界热带地区发病和死亡的主要传染病之一。用辐射减毒疟原虫子孢子（SPZ）免疫诱导的保护性免疫模型已成为阐明保护性免疫机制的框架和一种有前景的疫苗策略的原型。我们之前曾报道，尽管基于针对红细胞前期抗原（特别是环子孢子蛋白和子孢子表面蛋白2）的抗体和CD8 + 细胞溶解性T淋巴细胞反应被认为具有阶段特异性，但恶性疟原虫减毒SPZ在人类中诱导的保护性免疫也可能涉及CD4 + T细胞对寄生红细胞（pRBC）上存在的抗原作出反应。在本研究中，我们通过比较免疫前、保护诱导期和SPZ感染期个体的CD4 + T细胞体外pRBC刺激反应，研究了对pRBC作出反应的CD4 + T细胞的功能作用。本文报道的结果证实了先前发表的观察结果，即与pRBC相关的抗原在暴露于疟原虫衍生抗原的受试者而非未接触过疟疾的个体中诱导增殖性CD4 + 淋巴细胞反应；然而，现在我们证明pRBC增殖性CD4 + T细胞与保护性免疫并不一致。同样，pRBC诱导的IFN-γ水平并不能区分受保护的疟疾患者和易感人群，尽管仅在暴露于疟原虫的志愿者的淋巴细胞培养物中观察到IFN-γ，而在未接触过疟疾的个体的淋巴细胞培养物中未观察到。相比之下，我们注意到与未接触过疟疾的个体和出现寄生虫血症的受试者相比，来自受保护疟疾患者的培养物中产生IL-4的CD4 + T细胞增加，这些细胞还表现出记忆表型CD45RO和CD25表达上调。因此，这些观察结果表明，以CD45RO和CD25表达以及IL-4产生为特征的记忆性CD4 + T细胞亚群的诱导与减毒SPZ免疫产生的保护性免疫反应一致。
