Data_Sheet_4_Infection-Induced Resistance to Experimental Cerebral Malaria Is Dependent Upon Secreted Antibody-Mediated Inhibition of Pathogenic CD8+ T Cell Responses.PDF

Cerebral malaria (CM) is one of the most severe complications of Plasmodium falciparum infection. There is evidence that repeated parasite exposure promotes resistance against CM. However, the immunological basis of this infection-induced resistance remains poorly understood. Here, utilizing the Plasmodium berghei ANKA (PbA) model of experimental cerebral malaria (ECM), we show that three rounds of infection and drug-cure protects against the development of ECM during a subsequent fourth (4X) infection. Exposure-induced resistance was associated with specific suppression of CD8+ T cell activation and CTL-related pathways, which corresponded with the development of heterogeneous atypical B cell populations as well as the gradual infection-induced generation and maintenance of high levels of anti-parasite IgG. Mechanistically, transfer of high-titer anti-parasite IgG did not protect 1X infected mice against ECM and depletion of atypical and regulatory B cells during 4X infection failed to abrogate infection-induced resistance to ECM. However, IgMi mice that were unable to produce secreted antibody, or undergo class switching, during the repeated rounds of infection failed to develop resistance against ECM. The failure of infection-induced protection in IgMi mice was associated with impaired development of atypical B cell populations and the inability to suppress pathogenic CD8+ T cell responses. Our results, therefore, suggest the importance of anti-parasite antibody responses, gradually acquired, and maintained through repeated Plasmodium infections, for modulating the B cell compartment and eventually suppressing memory CD8+ T cell reactivation to establish infection-induced resistance to ECM.

脑型疟疾（Cerebral malaria, CM）是恶性疟原虫（Plasmodium falciparum）感染最严重的并发症之一。现有研究证实，反复的寄生虫暴露可增强机体对脑型疟疾的抵抗能力，但该感染诱导性抵抗的免疫学基础仍未明确。本研究借助实验性脑型疟疾（experimental cerebral malaria, ECM）的伯氏疟原虫ANKA株（Plasmodium berghei ANKA, PbA）感染模型，证实经过三轮感染并经药物治愈的小鼠，在后续第四次（4X）感染中可免受实验性脑型疟疾的侵袭。
暴露诱导的抵抗效应与CD8阳性T细胞（CD8+ T cell）活化及细胞毒性T淋巴细胞（cytotoxic T lymphocyte, CTL）相关通路的特异性抑制密切相关，同时伴随异质性非典型B细胞群的形成，以及感染逐步诱导产生并维持高水平抗寄生虫IgG（anti-parasite IgG）的过程。
机制研究显示，输注高滴度抗寄生虫IgG无法保护单次感染（1X）的小鼠免受脑型疟疾侵袭；而在第四次感染期间清除非典型B细胞与调节性B细胞（regulatory B cells），也无法消除感染诱导的脑型疟疾抵抗。不过，在反复感染过程中无法产生分泌型抗体或发生抗体类别转换（class switching）的IgMi小鼠，则未能获得对脑型疟疾的抵抗能力。
IgMi小鼠中感染诱导的保护作用缺失，与非典型B细胞群发育受损以及无法抑制致病性CD8阳性T细胞应答相关。综上，本研究结果表明，通过反复疟原虫感染逐步获得并维持的抗寄生虫抗体应答，对于调控B细胞库、最终抑制记忆性CD8阳性T细胞（memory CD8+ T cell）活化，从而建立感染诱导的实验性脑型疟疾抵抗具有重要意义。