日前，中科大免疫所田志剛教授課題組在乙肝病毒（HBV）耐受及天然免疫研究領(lǐng)域取得重要進展。他們發(fā)現(xiàn)乙肝患者NK細(xì)胞高表達抑制性受體NKG2A,，抗體阻斷NKG2A信號能夠使NK細(xì)胞功能恢復(fù)從而達到清除乙肝病毒的目的,。
HBV感染是世界范圍內(nèi)的科學(xué)難題，目前依賴于干擾素與核苷類似物常規(guī)治療方法不能徹底清除病毒,。本研究發(fā)現(xiàn),，活化期的慢性乙肝攜帶者外周血NK細(xì)胞表面NKG2A受體的表達明顯高于健康人，而抗體阻斷NKG2A可以顯著提高乙肝攜帶者NK細(xì)胞的體外細(xì)胞毒性,。為了進行更深入的機制研究,，本研究引入HBV攜帶小鼠模型, 此小鼠模型展示出與人類HBV攜帶者非常類似的現(xiàn)象—其NK細(xì)胞特別是肝臟NK細(xì)胞表面NKG2A分子高表達,。進一步的機制研究發(fā)現(xiàn)，HBV感染會誘導(dǎo)小鼠肝臟局部產(chǎn)生一群具有調(diào)節(jié)功能的CD4+T細(xì)胞,，其分泌的IL-10能夠顯著上調(diào)NK細(xì)胞NKG2A的表達進而抑制NK細(xì)胞的功能,。更為重要的是，在HBV攜帶小鼠體內(nèi)利用抗體阻斷NKG2A信號可以顯著促進小鼠清除HBV病毒,。
該研究成果于2012年10月以題為“Blocking the Natural Killer (NK) Cell Inhibitory Receptor NKG2A Increases Activity of Human NK Cells and Clears HBV Infection in Mice”發(fā)表在國際著名學(xué)術(shù)期刊Gastroenterology上,。雜志編委指出“本研究揭示了通過阻斷NKG2A進而清除HBV感染的生物學(xué)原理，具有重要的科研及臨床意義,。”（生物谷Bioon.com）
doi: 10.1053/j.gastro.2012.10.039
PMC:
PMID:
Blocking the Natural Killer (NK) Cell Inhibitory Receptor NKG2A Increases Activity of Human NK Cells and Clears HBV Infection in Mice
Li F, Wei H, Wei H, Gao Y, Xu L, Yin W, Sun R, Tian Z.
BACKGROUND & AIMS:: We studied the functions of natural killer (NK) cells and the role of the NK cell inhibitory receptor (NKG2A) during hepatitis B virus (HBV) infection in patients and mice. METHODS:: We analyzed levels of NKG2A on peripheral blood NK cells from 42 patients with active chronic hepatitis B (CHB), 31 patients with inactive CHB, and 35 healthy volunteers (controls). Five patients with CHB treated with anti-viral therapy were also included, to evaluate changes in NK cells after HBV titers decreased. We examined the effects of blocking antibodies against NKG2A, or its ligand Qa-1 (equivalent to HLA-E in humans), in immunocompetent mice that express HBV from a plasmid and are positive for serum hepatitis B surface antigen (a mouse model of HBV infection). RESULTS:: A higher percentage of NK cells from patients with active CHB were positive for NKG2A (38.47%) than from patients with inactive CHB (19.33%; P <.01) or controls (27.96%, P <.05). The percentage of NKG2A+ cells correlated with serum viral load (r=0.5457, P <.001). The percentage of NKG2A+ cells decreased along with HBV load in patients that received anti-viral therapy ( P <.05). Blocking NKG2A interaction with HLA-E in peripheral NK cells from patients with active CHB increased their cytotoxicity in vitro. NK cells of HBV carrier mice also had higher percentages of NK cells that expressed NKG2A compared with control mice; NKG2A was likely to be upregulated by production of interleukin-10 by hepatic regulatory CD4+CD25+ T cells. Blocking Qa-1 in these mice promoted viral clearance in an NK cell-dependent manner. CONCLUSIONS:: Infection with HBV increases levels of the inhibitory receptor NKG2A on NK cells in mice and humans, and reduces their ability to clear HBV. Reagents designed to block the interaction between NKG2A and HLA-E might be developed to treat CHB infection
