Trypanosoma brucei Co-opts NK Cells to Kill Splenic B2 B Cells.
Trypanosoma brucei Co-opts NK Cells to Kill Splenic B2 B Cells.
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DOI：
10.1371/journal.ppat.1005733
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发表时间：
2016-07
期刊：
影响因子：
6.7
通讯作者：
Black SJ
中科院分区：
文献类型：
--
作者：
Frenkel D;Zhang F;Guirnalda P;Haynes C;Bockstal V;Radwanska M;Magez S;Black SJ
感染T.布鲁氏菌AnTat 1.1，C57 BL/6小鼠丧失脾B2 B细胞和淋巴滤泡，产生较差的寄生虫特异性抗体应答，体重减轻，贫血并在35天内死于暴发性寄生虫血症。相比之下，缺乏细胞毒性颗粒孔形成蛋白穿孔素（Prf 1-/-）的感染C57 BL/6小鼠保留了脾B2 B细胞和淋巴滤泡，对许多锥虫多肽产生了高滴度抗体应答，迅速抑制了寄生虫血症，并且至少60天内没有发生贫血或体重减轻。多条证据表明T.布鲁氏菌感染诱导的脾B细胞耗竭由自然杀伤（NK）细胞介导的细胞毒性引起：i）从感染的完整、T细胞缺陷（TCR -/-）和FcγRIIIa缺陷（CD 16-/-）C57 BL/6小鼠的脾中耗竭B2 B细胞，不需要T细胞、NKT细胞或抗体依赖性细胞介导的细胞毒性; ii）施用NK1.1特异性IgG 2a（mAb PK 136），但非无关IgG 2a（骨髓瘤M9144）防止感染诱导的B细胞耗竭，这与对NK细胞的需求一致; iii）在感染的C57 BL/6小鼠中脾NK细胞而不是T细胞或NKT细胞脱颗粒，伴随B细胞耗竭，由CD 107 a的表面表达增加证明; iv）来自未处理C57 BL/6小鼠的纯化NK细胞杀死来自T.在体外感染布氏杆菌但未感染的小鼠中，表明感染后B细胞获得NK细胞活化表型; v）过继转移的C57 BL/6 NK细胞防止感染的Prf 1-/-小鼠中感染诱导的B细胞群体生长，这与体内B细胞杀伤一致; vi）感染小鼠中的脱颗粒NK细胞具有改变的基因和分化抗原表达，并且丧失与功能耗竭一致的细胞毒活性，但随着感染的进展数量增加，表明继续产生。结论T.布氏杆菌感染的小鼠杀死B细胞、抑制体液免疫并加速早期死亡。感染非洲锥虫的锥虫易感哺乳动物会出现贫血、体重减轻、免疫能力丧失，并对继发感染的易感性增加。我们在T. B.非洲锥虫的布氏AnTat 1.1小鼠模型显示，感染诱导的体液免疫能力丧失与脾移行区、边缘区和滤泡B细胞的耗竭相关。在这里，我们表明，脾B2 B细胞在感染的小鼠锥虫波缓解后获得NK细胞活化表型，并删除抗体无关，脾NK细胞介导的细胞毒性，这是一个穿孔素依赖的过程。在没有这种杀戮过程的情况下，即，穿孔素基因敲除小鼠T.布氏杆菌感染不引起脾B细胞的耗竭、脾结构的破坏、贫血、体重减轻或早期死亡，并且确实引起高滴度的锥虫多肽特异性抗体应答。研究表明，T.布氏杆菌选择宿主NK细胞以降解适应性免疫系统的抗体分支并引发危及生命的锥虫病。
After infection with T. brucei AnTat 1.1, C57BL/6 mice lost splenic B2 B cells and lymphoid follicles, developed poor parasite-specific antibody responses, lost weight, became anemic and died with fulminating parasitemia within 35 days. In contrast, infected C57BL/6 mice lacking the cytotoxic granule pore-forming protein perforin (Prf1 -/-) retained splenic B2 B cells and lymphoid follicles, developed high-titer antibody responses against many trypanosome polypeptides, rapidly suppressed parasitemia and did not develop anemia or lose weight for at least 60 days. Several lines of evidence show that T. brucei infection-induced splenic B cell depletion results from natural killer (NK) cell-mediated cytotoxicity: i) B2 B cells were depleted from the spleens of infected intact, T cell deficient (TCR -/-) and FcγRIIIa deficient (CD16-/-) C57BL/6 mice excluding a requirement for T cells, NKT cell, or antibody-dependent cell-mediated cytotoxicity; ii) administration of NK1.1 specific IgG2a (mAb PK136) but not irrelevant IgG2a (myeloma M9144) prevented infection-induced B cell depletion consistent with a requirement for NK cells; iii) splenic NK cells but not T cells or NKT cells degranulated in infected C57BL/6 mice co-incident with B cell depletion evidenced by increased surface expression of CD107a; iv) purified NK cells from naïve C57BL/6 mice killed purified splenic B cells from T. brucei infected but not uninfected mice in vitro indicating acquisition of an NK cell activating phenotype by the post-infection B cells; v) adoptively transferred C57BL/6 NK cells prevented infection-induced B cell population growth in infected Prf1-/- mice consistent with in vivo B cell killing; vi) degranulated NK cells in infected mice had altered gene and differentiation antigen expression and lost cytotoxic activity consistent with functional exhaustion, but increased in number as infection progressed indicating continued generation. We conclude that NK cells in T. brucei infected mice kill B cells, suppress humoral immunity and expedite early mortality. Trypanosomiasis-susceptible mammals that are infected with African trypanosomes develop anemia, lose weight, lose immune competence and have an increased susceptibility to secondary infections. Our earlier studies in the T. b. brucei AnTat 1.1 mouse model of African trypanosomiasis show that infection-induced loss of humoral immune competence correlates with depletion of splenic transitional, marginal zone and follicular B cells. Here, we show that splenic B2 B cells in the infected mice acquire an NK cell activating phenotype after trypanosome wave remission and are deleted by antibody-independent, splenic NK cell-mediated cytotoxicity, which is a perforin dependent process. In the absence of this killing process, i.e., in perforin gene knock out mice, T. brucei infection did not cause depletion of splenic B cells, or disruption of splenic architecture, or anemia, or weight loss, or early mortality and did elicit high-titer trypanosome polypeptide-specific antibody responses. The studies show that T. brucei co-opts host NK cells to degrade the antibody limb of the adaptive immune system and elicit life-threatening trypanosomiasis pathology.