自然殺傷細(xì)胞（Nature KillerCell，NK）是機體重要的免疫細(xì)胞，尤其在抗擊腫瘤的過程中發(fā)揮重要的作用。來自骨髓的抑制性細(xì)胞（myeloid-derivedsuppressorcells，MDSC），一類表達(dá)CD11b+Gr-1+的髓樣細(xì)胞，在腫瘤發(fā)生的過程中出現(xiàn)異常的過度表達(dá)現(xiàn)象，大量的MDSC細(xì)胞能抑制T細(xì)胞和樹突狀細(xì)胞發(fā)揮免疫活性，導(dǎo)致腫瘤細(xì)胞可逃避免疫系統(tǒng)。然而，MDSC細(xì)胞對NK細(xì)胞天然免疫功能的調(diào)節(jié)作用還有待深入調(diào)查研究。
在本研究中，曹雪濤院士研究小組對該問題進行研究，將腫瘤移植到動物模型中，結(jié)果發(fā)現(xiàn)，MDSC細(xì)胞對肝臟和脾臟中的NK細(xì)胞具有強大的抑制作用，使得NK細(xì)胞無法發(fā)揮天然免疫功能，這些結(jié)果表明，腫瘤損傷肝臟中的NK細(xì)胞是一個普遍的現(xiàn)象。研究小組接下來研究肝癌移植小鼠模型，探索肝臟NK細(xì)胞如何受到損壞。
結(jié)果發(fā)現(xiàn)，肝臟和脾臟中的MDSC細(xì)胞與NK細(xì)胞的關(guān)系，當(dāng)MDSC細(xì)胞增多則NK細(xì)胞的免疫功能下降。MDSC能抑制NK細(xì)胞表達(dá)細(xì)胞毒性標(biāo)志NKG2D以及IFN-γ。此外，MDSC細(xì)胞抑制Nk細(xì)胞的能力由細(xì)胞膜表面的TGF-β1來控制。研究還發(fā)現(xiàn)，當(dāng)MDSC細(xì)胞減少時，NK細(xì)胞的功能可逐步得到恢復(fù)，但是調(diào)節(jié)性T細(xì)胞對NK細(xì)胞的作用卻不因調(diào)節(jié)性T細(xì)胞的減少而得到恢復(fù)。
這些研究結(jié)果表明，MDSC細(xì)胞通過TGF-β1誘導(dǎo)NK細(xì)胞失去功能。這也說明，MDSC細(xì)胞而不是調(diào)節(jié)性T細(xì)胞是NK細(xì)胞的負(fù)功能調(diào)節(jié)因子。研究結(jié)果為腫瘤逃避免疫系統(tǒng)提供了新的視野。
該研究項目受到國家自然科學(xué)基金資助。（生物谷Bioon.com）
生物谷推薦原始出處：
The Journal of Immunology , 2009, 182: 240-249.
Cancer-Expanded Myeloid-Derived Suppressor Cells Induce Anergy of NK Cells through Membrane-Bound TGF-β11
Hequan Li2,*, Yanmei Han2,, Qiuli Guo, Minggang Zhang and Xuetao Cao3,*,
* Institute of Immunology, Zhejiang University School of Medicine,Hangzhou, and Institute of Immunology and National Key Laboratory ofMedical Immunology, Second Military Medical University, Shanghai,Peoples Republic of China
NK cells, the important effector of innate immunity, play criticalroles in the antitumor immunity. Myeloid-derived suppressor cells(MDSC), a population of CD11b+Gr-1+ myeloid cells expanded dramaticallyduring tumor progression, can inhibit T cells and dendritic cells,contributing to tumor immune escaper. However, regulation of NK cellinnate function by MDSC in tumor-bearing host needs to be investigated.In this study, we found that the function of NK cells from liver andspleen was impaired significantly in all tumor-bearing models,indicating the impairment of hepatic NK cell function by tumor is auniversal phenomenon. Then we prepared the orthotopic livercancer-bearing mice as tumor model to investigate how hepatic NK cellsare impaired. We show that down-regulation of NK cell function isinversely correlated with the marked increase of MDSC in liver andspleen. MDSC inhibit cytotoxicity, NKG2D expression, and IFN- productionof NK cells both in vitro and in vivo. After incubation with MDSC, NKcells could not be activated to produce IFN-. Furthermore,membrane-bound TGF-β1 on MDSC is responsible for MDSC-mediatedsuppression of NK cells. The impaired function of hepatic NK cells inorthotopic liver cancer-bearing mice could be restored by depletion ofMDSC, but not regulatory T cells. Therefore, cancer-expanded MDSC caninduce anergy of NK cells via membrane-bound TGF-β1. MDSC, but notregulatory T cells, are main negative regulator of hepatic NK cellfunction in tumor-bearing host. Our study provides new mechanisticexplanations for tumor immune escape.
