肝脏微环境对肝脏NK和NKT细胞发育的影响

发布时间：2018-08-20 19:00

【摘要】：NK细胞和NKT细胞前体来源于骨髓细胞,定向分化至自然杀伤细胞谱系,并发育成具有效应功能和异质性表型的成熟的NK细胞和NKT细胞。骨髓,胚胎胸腺,淋巴结,肝脏,脾脏和外周血中都可以检测到自然杀伤细胞前体；但是不成熟自然杀伤细胞(iNK)只能在骨髓,肝脏和脾脏中被检测到。这些发育中间体是如何离开骨髓在外周位点如肝脏、脾脏中完成发育成熟的过程仍然未知。肝脏中存在不成熟的NK细胞和NKT细胞。肝脏中不成熟的NK细胞具有特殊的表型,即持续性表达肿瘤坏死因子相关凋亡诱导配体(tumour necrosis factor-related apoptosis-inducing ligand, TRAIL),但是低水平表达其他成熟自然杀伤细胞表面标志,例如Ly49受体和CD11b.胸腺中不成熟NKT细胞不表达NK1.1标志,在外周经历发育分化成熟后表达NKl.1。肝脏是外周NKT细胞发育成熟的重要场所。在NK细胞和NKT细胞发育分化过程中,不同组织脏器中基质细胞通过分泌可溶性细胞因子等信号分子来影响其表型和功能。本研究主要使用流式细胞术探索了小鼠个体发生过程中肝脏中NK细胞的发育并且与脾脏NK细胞发育进行了比对。Y干扰素对肝脏NK细胞亚群分布以及功能的影响做了初步的研究。我们发现,CD27-CD11b-NK细胞前体主要聚集在成年小鼠肝脏而不是脾脏中小鼠个体发生时,在肝脏中,存在更多的不成熟的NK细胞,表达高水平的NKG2A和低水平的Ly49受体。肝脏中NK细胞表面刺激性受体和粘附分子的表达也与脾脏NK细胞不同。这些结果显示了肝脏内存在特异的NK细胞发育途径,并且环境微环境在NK细胞发育分化过程中起了重要作用。我们揭示出成年Y干扰素缺陷小鼠肝脏内成熟NK细胞的比例和数目都显著减少了。成年γ干扰素缺陷小鼠肝脏内聚集了特异的NK细胞亚群和表型。然而,成年Y干扰素缺陷小鼠肝脏和骨髓内Lin-CD122+NK前体细胞比例和数目都是正常的。进一步研究发现,γ干扰素缺陷导致小鼠肝脏内NK细胞活化分子CD69和功能分子的表达减弱。这些结果揭示了γ干扰素在维持肝脏独特微环境,影响肝脏NK细胞发育中起了重要作用。另外,我们发现肝脏中存在不成熟的NKT细胞亚群。对于小鼠个体发生时肝脏中NKT细胞发育阶段及亚群变化做了初步探索。
[Abstract]:NK cells and NKT cells derived from bone marrow cells differentiated into natural killer cell lineages and developed into mature NK cells and NKT cells with functional and heterogeneous phenotypes. Precursors of natural killer cells can be detected in bone marrow, embryonic thymus, lymph nodes, liver, spleen and peripheral blood, but (iNK) can only be detected in bone marrow, liver and spleen. How these developmental intermediates leave the bone marrow at peripheral sites such as liver and spleen is still unknown. Immature NK cells and NKT cells exist in the liver. Immature NK cells in the liver have special phenotypes, i.e., the expression of tumor necrosis factor-related apoptosis-inducing ligands (tumour necrosis factor-related apoptosis-inducing ligand, TRAIL),) but low level expression of other mature natural killer cell surface markers, such as Ly49 receptor and CD11b. Immature NKT cells in thymus do not express NK1.1 markers, but NKl.1after development, differentiation and maturation. Liver is an important site for the development and maturation of peripheral NKT cells. During the development and differentiation of NK cells and NKT cells, stromal cells in different tissues affect their phenotypes and functions by secreting signal molecules such as soluble cytokines. In this study, flow cytometry was used to explore the development of NK cells in the liver of mice during ontogenesis and the effects of interferon Y on the distribution and function of NK cell subsets in the liver were compared with those in the spleen. We found that the precursor of CD27-CD11b-NK cells was mainly concentrated in the adult mouse liver, but not in the spleen of mice. In the liver, there were more immature NK cells, high level of NKG2A and low level of Ly49 receptor. The expression of irritant receptors and adhesion molecules on NK cells was also different from that in spleen NK cells. These results suggest that there is a specific NK cell development pathway in the liver and that the environmental microenvironment plays an important role in the development and differentiation of NK cells. We revealed that the proportion and number of mature NK cells in the liver of adult IFN- Y deficient mice decreased significantly. Specific NK cell subsets and phenotypes were found in the liver of adult IFN- 纬 deficient mice. However, the proportion and number of Lin-CD122 NK progenitor cells in liver and bone marrow of adult interferon Y deficient mice were normal. Furthermore, it was found that the deficiency of interferon 纬 resulted in a decrease in the expression of NK cell activating molecules CD69 and functional molecules in the liver of mice. These results suggest that interferon-纬 plays an important role in maintaining the unique microenvironment of the liver and affecting the development of NK cells in the liver. In addition, we found immature subsets of NKT cells in the liver. The developmental stages and subsets of NKT cells in the liver of mice during ontogenesis were preliminarily explored.
【学位授予单位】：中国科学技术大学
【学位级别】：博士
【学位授予年份】：2011
【分类号】：R392

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