Repeated Plasmodium falciparum infections drive the development of clinical immunity to malaria in humans; however, the immunological mechanisms that underpin this response are only partially understood. We investigated the impact of repeated P. falciparum infections on human γδ T cells in the context of natural infection in Malian children and adults, as well as serial controlled human malaria infection (CHMI) of U.S. adults, some of whom became clinically immune to malaria. In contrast to the predominant Vδ2⁺ T cell population in malaria-naïve Australian individuals, clonally expanded cytotoxic Vδ1_effector T cells were enriched in the γδ T cell compartment of Malian subjects. Malaria-naïve U.S. adults exposed to four sequential CHMIs defined the precise impact of P. falciparum on the γδ T cell repertoire. Specifically, innate-like Vδ2⁺ T cells exhibited an initial robust polyclonal response to P. falciparum infection that was not sustained with repeated infections, whereas Vδ1⁺ T cells increased in frequency with repeated infections. Moreover, repeated P. falciparum infection drove waves of clonal selection in the Vδ1⁺ T cell receptor repertoire that coincided with the differentiation of Vδ1_naïve T cells into cytotoxic Vδ1_effector T cells. Vδ1⁺ T cells of malaria-exposed Malian and U.S. individuals were licensed for reactivity to P. falciparum parasites in vitro. Together, our study indicates that repeated P. falciparum infection drives the clonal expansion of an adaptive γδ T cell repertoire and establishes a role for Vδ1⁺ T cells in the human immune response to malaria.

中文翻译：

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人类反复感染恶性疟原虫会导致适应性 γδ T 细胞库的克隆扩增

反复的恶性疟原虫感染推动了人类对疟疾的临床免疫力的发展；然而，支持这种反应的免疫机制只是部分了解。我们研究了在马里儿童和成人自然感染的情况下，恶性疟原虫反复感染对人类 γδ T 细胞的影响，以及美国成年人连续受控人类疟疾感染 (CHMI)，其中一些人对疟疾具有临床免疫力. 与未感染疟疾的澳大利亚个体中主要的 Vδ2 ^{+ T 细胞群相比，克隆扩增的细胞毒性 Vδ1}_效应子T 细胞在马里受试者的 γδ T 细胞区室中富集。接触过四种连续 CHMI 的未感染过疟疾的美国成年人确定了恶性疟原虫对 γδ T 细胞库的精确影响。具体而言，先天样 Vδ2 ^{+ T 细胞表现出对}恶性疟原虫感染的初始强烈多克隆反应，这种反应不会因反复感染而持续，而 Vδ1 ⁺ T 细胞的频率随着反复感染而增加。此外，重复的恶性疟原虫感染驱动了 Vδ1 ⁺ T 细胞受体库中的克隆选择浪潮，这与 Vδ1_幼稚T 细胞分化为细胞毒性 Vδ1_{效应子一致}T 细胞。暴露于疟疾的马里和美国个体的Vδ1 ⁺ T 细胞被许可在体外对恶性疟原虫寄生虫产生反应。总之，我们的研究表明，反复的恶性疟原虫感染驱动了适应性 γδ T 细胞库的克隆扩增，并确立了 Vδ1 ⁺ T 细胞在人体对疟疾的免疫反应中的作用。