被恶性疟原虫感染的红细胞（iRBC）在早期的免疫反应中，自然杀伤细胞(Natural killer cell，也译作NK细胞)是被激活的，这表明NK细胞与先天性抗寄生虫免疫反应有关。然而，NK细胞是否会直接识别iRBC，刺激iRBC是否需要辅助细胞呈递信号或是溶解性因子，这些问题目前还不明确。
近日，德国蒂宾根大学热带医学研究所 Meral Esen等人发现：被疟原虫感染的红细胞会通过宿主表达Hsp70来引起NK细胞释放颗粒酶B，结果被感染的红细胞衰亡。相关论文发表在3月15日的美国《公共科学图书馆—综合》（PLoS One）上。
在近期的研究中，研究人员开展了关于“宿主细胞膜偶联的热休克蛋白70（Hsp70）会引起NK细胞对iRBC的毒性”的研究，这些NK细胞来自与疟疾病人捐赠的NK细胞以及培养的NK92细胞系。对于表达于iRBC细胞膜的Hsp70和HLA-E，以及可能性的活化的NK细胞受体(包括NKG2C和CD94)，该研究运用了流式细胞术以及免疫印记对它们进行评估。
蛋白印迹、RT-PCR 以及ELISPOT分析表明：颗粒酶B(GzmB)的产生及释放都由没有受过刺激的NK细胞，以及Hsp70肽(TKD)预先刺激的NK细胞所启动。
研究结果表明，当iRBC细胞上没有HLA-E却有Hsp70时，会促进感染的宿主细胞成为了NK细胞调停的细胞毒性目标。iRBC与NK细胞的联系则引起了GzmB的释放，当GzmB被摄取后，iRBC通过一个不依赖穿孔素而是由GzmB调节的机制导致衰亡。
结果表明，NK细胞对iRBC的活性可以被TKD肽特异性增强，也可以因为Hsp70被抑制而降低到基础水平。因此，TKD可以作为一个革新性的免疫刺激物。（生物谷Bioon.com）
doi: 10.1371/journal.pone.0033774
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Plasmodium falciparum-Infected Erythrocytes Induce Granzyme B by NK Cells through Expression of Host-Hsp70
Evelyn Bttger, Gabriele Multhoff, Jürgen F. J. Kun, Meral Esen
In the early immune response to Plasmodium falciparum-infected erythrocytes (iRBC), Natural Killer (NK) cells are activated, which suggests an important role in innate anti-parasitic immunity. However, it is not well understood whether NK cells directly recognize iRBC or whether stimulation of NK cells depends mainly on activating signals from accessory cells through cell-to-cell contact or soluble factors.In the present study, we investigated the influence of membrane-bound host Heat shock protein (Hsp) 70 in triggering cytotoxicity of NK cells from malaria-nave donors or the cell line NK92 against iRBC. Hsp70 and HLA-E membrane expression on iRBC and potential activatory NK cell receptors (NKG2C, CD94) were assessed by flow cytometry and immunoblot. Upon contact with iRBC, Granzyme B (GzmB) production and release was initiated by unstimulated and Hsp70-peptide (TKD) pre-stimulated NK cells, as determined by Western blot, RT-PCR and ELISPOT analysis. Eryptosis of iRBC was determined by Annexin V-staining.Our results suggest that presence of Hsp70 and absence of HLA-E on the membrane of iRBC prompt the infected host cells to become targets for NK cell-mediated cytotoxicity, as evidenced by impaired parasite development. Contact of iRBC with NK cells induced release of GzmB. We propose that following GzmB uptake, iRBC undergo eryptosis via a perforin-independent, GzmB-mediated mechanism.Since NK activity toward iRBC could be specifically enhanced by TKD peptide and abrogated to baseline levels by blocking Hsp70 exposure, we propose TKD as an innovative immunostimulatory agent to be tested as an adjunct to anti-parasitic treatments in vivo.
