Figueiredo Maria Marta, Costa Pedro Augusto Carvalho, Diniz Suelen Queiroz, Henriques Priscilla Miranda, Kano Flora Satiko, Tada Mauro Sugiro, Pereira Dhelio Batista, Soares Irene Silva, Martins-Filho Olindo Assis, Jankovic Dragana, Gazzinelli Ricardo Tostes, Antonelli Lis Ribeiro do Valle
Laboratório de Biologia e Imunologia de Doenças Infecciosas e Parasitárias, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Laboratório de Imunopatologia, Instituto René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
PLoS Pathog. 2017 Jul 10;13(7):e1006484. doi: 10.1371/journal.ppat.1006484. eCollection 2017 Jul.
Although the importance of humoral immunity to malaria has been established, factors that control antibody production are poorly understood. Follicular helper T cells (Tfh cells) are pivotal for generating high-affinity, long-lived antibody responses. While it has been proposed that expansion of antigen-specific Tfh cells, interleukin (IL) 21 production and robust germinal center formation are associated with protection against malaria in mice, whether Tfh cells are found during Plasmodium vivax (P. vivax) infection and if they play a role during disease remains unknown. Our goal was to define the role of Tfh cells during P. vivax malaria. We demonstrate that P. vivax infection triggers IL-21 production and an increase in Tfh cells (PD-1+ICOS+CXCR5+CD45RO+CD4+CD3+). As expected, FACS-sorted Tfh cells, the primary source of IL-21, induced immunoglobulin production by purified naïve B cells. Furthermore, we found that P. vivax infection alters the B cell compartment and these alterations were dependent on the number of previous infections. First exposure leads to increased proportions of activated and atypical memory B cells and decreased frequencies of classical memory B cells, whereas patients that experienced multiple episodes displayed lower proportions of atypical B cells and higher frequencies of classical memory B cells. Despite the limited sample size, but consistent with the latter finding, the data suggest that patients who had more than five infections harbored more Tfh cells and produce more specific antibodies. P. vivax infection triggers IL-21 production by Tfh that impact B cell responses in humans.
尽管体液免疫对疟疾的重要性已得到证实，但控制抗体产生的因素仍知之甚少。滤泡辅助性T细胞（Tfh细胞）对于产生高亲和力、长寿的抗体反应至关重要。虽然有人提出抗原特异性Tfh细胞的扩增、白细胞介素（IL）-21的产生以及强大的生发中心形成与小鼠抗疟疾保护有关，但间日疟原虫（P. vivax）感染期间是否存在Tfh细胞以及它们在疾病过程中是否发挥作用仍不清楚。我们的目标是确定Tfh细胞在间日疟原虫疟疾中的作用。我们证明，间日疟原虫感染会触发IL-21的产生以及Tfh细胞（PD-1+ICOS+CXCR5+CD45RO+CD4+CD3+）的增加。正如预期的那样，通过荧光激活细胞分选（FACS）分离的Tfh细胞（IL-21的主要来源）可诱导纯化的幼稚B细胞产生免疫球蛋白。此外，我们发现间日疟原虫感染会改变B细胞区室，并且这些改变取决于既往感染的次数。首次感染会导致活化和非典型记忆B细胞比例增加，经典记忆B细胞频率降低，而经历多次发作的患者非典型B细胞比例较低，经典记忆B细胞频率较高。尽管样本量有限，但与后一项发现一致，数据表明感染超过五次的患者体内Tfh细胞更多，产生的特异性抗体也更多。间日疟原虫感染会触发Tfh细胞产生IL-21，从而影响人类的B细胞反应。
