浙江大學醫(yī)學院免疫學系特聘教授,，浙江大學醫(yī)學院免疫學研究所所長,，第二軍醫(yī)大醫(yī)學院教授曹雪濤院士繼08年歲末在《血液》（Blood）發(fā)表免疫學成果后,，2009年開年又于《免疫學雜志》（The Journal of Immunology）發(fā)表文章,。
自然殺傷細胞（Nature Killer Cell,，NK）是機體重要的免疫細胞,，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胞（myeloid-derived suppressor cells,，MDSC），一類表達CD11b+Gr-1+的髓樣細胞，在腫瘤發(fā)生的過程中出現異常的過度表達現象,，大量的MDSC細胞能抑制T細胞和樹突狀細胞發(fā)揮免疫活性,，導致腫瘤細胞可逃避免疫系統(tǒng)。然而,，MDSC細胞對NK細胞天然免疫功能的調節(jié)作用還有待深入調查研究,。
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,，結果發(fā)現，MDSC細胞對肝臟和脾臟中的NK細胞具有強大的抑制作用,，使得NK細胞無法發(fā)揮天然免疫功能,，這些結果表明，腫瘤損傷肝臟中的NK細胞是一個普遍的現象,。研究小組接下來研究肝癌移植小鼠模型,，探索肝臟NK細胞如何受到損壞。
結果發(fā)現,，肝臟和脾臟中的MDSC細胞與NK細胞的關系,，當MDSC細胞增多則NK細胞的免疫功能下降。MDSC能抑制NK細胞表達細胞毒性標志NKG2D以及IFN-γ,。此外,，MDSC細胞抑制Nk細胞的能力由細胞膜表面的TGF-β1來控制。研究還發(fā)現,，當MDSC細胞減少時,，NK細胞的功能可逐步得到恢復，但是調節(jié)性T細胞對NK細胞的作用卻不因調節(jié)性T細胞的減少而得到恢復,。
這些研究結果表明,，MDSC細胞通過TGF-β1誘導NK細胞失去功能。這也說明,，MDSC細胞而不是調節(jié)性T細胞是NK細胞的負功能調節(jié)因子,。研究結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 of Medical Immunology, Second Military Medical University, Shanghai, Peoples Republic of China
NK cells, the important effector of innate immunity, play critical roles in the antitumor immunity. Myeloid-derived suppressor cells (MDSC), a population of CD11b+Gr-1+ myeloid cells expanded dramatically during tumor progression, can inhibit T cells and dendritic cells, contributing to tumor immune escaper. However, regulation of NK cell innate function by MDSC in tumor-bearing host needs to be investigated. In this study, we found that the function of NK cells from liver and spleen was impaired significantly in all tumor-bearing models, indicating the impairment of hepatic NK cell function by tumor is a universal phenomenon. Then we prepared the orthotopic liver cancer-bearing mice as tumor model to investigate how hepatic NK cells are impaired. We show that down-regulation of NK cell function is inversely correlated with the marked increase of MDSC in liver and spleen. MDSC inhibit cytotoxicity, NKG2D expression, and IFN- production of NK cells both in vitro and in vivo. After incubation with MDSC, NK cells could not be activated to produce IFN-. Furthermore, membrane-bound TGF-β1 on MDSC is responsible for MDSC-mediated suppression of NK cells. The impaired function of hepatic NK cells in orthotopic liver cancer-bearing mice could be restored by depletion of MDSC, but not regulatory T cells. Therefore, cancer-expanded MDSC can induce anergy of NK cells via membrane-bound TGF-β1. MDSC, but not regulatory T cells, are main negative regulator of hepatic NK cell function in tumor-bearing host. Our study provides new mechanistic explanations for tumor immune escape.
