US Food and Drug Administration, Division of Bacterial Allergenic and Parasitic Diseases, Center for Biologics Evaluation and Research, Silver Spring, MD, United States.
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States.
Front Immunol. 2018 Nov 9;9:2612. doi: 10.3389/fimmu.2018.02612. eCollection 2018.
The delay in parasite-specific B cell development leaves people in malaria endemic areas vulnerable to repeated infections. Here, we investigated the role of transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), a molecule involved in the generation of antigen-specific antibody secreting cells, in host response to non-lethal infection. We found that TACI deficiency not only resulted in higher peak parasitemia levels in challenged mice, but also led to a delay in parasite clearance and anti- Merozoite Surface Protein 1(C-terminal 19-kDa fragment [rMSP-1]) protein and anti-rMSP-1 and anti- IgG antibody development. There was also a delay in the generation of splenic high affinity antibody secreting cells that recognize rMSP-1 protein as compared to wild-type mice. Interestingly, coinciding with the delay in parasite clearance there was a delay in the resolution of T follicular helper (T) cell and germinal center (GC) B cell responses in TACI -/- mice. The persistence of T and GC B cells is likely a result of enhanced interaction between T and GC B cells because inducible costimulator ligand (ICOSL) expression was significantly higher on TACI -/- GC B cells than wild-type cells. The difference in the kinetics of GC reaction appeared to also impact the emergence of plasma cells (PC) because there was a delay in the generation of TACI -/- mice PC. Nevertheless, following the recovery from infection, TACI -/- and wild-type mice were both protected from a rechallenge infection. Establishment of protective B cell response was responsible for the resolution of parasitemia because B cells purified from recovered TACI -/- or wild-type mice were equally protective when introduced to naïve wild-type mice prior to challenge. Thus, despite the increased susceptibility of TACI -/- mice to infection and a delay in the development of protective antibody levels, TACI -/- mice are able to clear the infection and resist rechallenge infection.
寄生虫特异性 B 细胞发育的延迟使疟疾流行地区的人们容易受到反复感染。在这里，我们研究了跨膜激活剂和钙调节剂及亲环素配体相互作用物（TACI）在宿主对非致死性感染的反应中的作用，TACI 是一种参与抗原特异性抗体分泌细胞生成的分子。我们发现 TACI 缺乏不仅导致感染挑战的小鼠中更高的峰值寄生虫血症水平，而且导致寄生虫清除和抗疟原虫表面蛋白 1（C 末端 19kDa 片段[rMSP-1]）蛋白以及抗 rMSP-1 和抗 IgG 抗体的产生延迟。与野生型小鼠相比，脾脏高亲和力抗体分泌细胞的产生也出现延迟，这些细胞可识别 rMSP-1 蛋白。有趣的是，与寄生虫清除延迟同时，TACI-/-小鼠的 T 滤泡辅助（Tfh）细胞和生发中心（GC）B 细胞反应的解决也出现延迟。T 和 GC B 细胞之间的相互作用增强，导致 T 和 GC B 细胞的持续存在，因为诱导性共刺激配体（ICOSL）在 TACI-/-GC B 细胞上的表达明显高于野生型细胞。GC 反应动力学的差异似乎也影响浆细胞（PC）的出现，因为 TACI-/-小鼠 PC 的产生出现延迟。尽管如此，在从感染中恢复后，TACI-/-和野生型小鼠都受到保护免受再感染。保护性 B 细胞反应的建立是寄生虫血症消退的原因，因为从恢复的 TACI-/-或野生型小鼠中纯化的 B 细胞在引入到之前未感染的野生型小鼠之前，对寄生虫血症的消退同样具有保护作用。因此，尽管 TACI-/-小鼠对感染的易感性增加，并且保护性抗体水平的产生延迟，但 TACI-/-小鼠能够清除感染并抵抗再感染。
