人类上皮性卵巢癌细胞培养上清诱导CD4+CD25-CD45RA+初始T细胞向调节性T细胞转化的研究

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英文题名：Supernatant of Human Epithelial Ovarian Carcinoma Cell Culture Induces CD4+CD25-CD45RA+ Na(?)ve T Cells to Develop into Regulatory T Cells in Vitro 作者：赵小峰 论文级别：博士 学科专业名称：妇产科学 中文关键词：CD4 ; T细胞 ; 初始T细胞 ; 激活 ; 叉头框蛋白3 ; 调节性T细胞 ; 记忆性T细胞 ; 叉头框蛋白3 ; 凋亡 ; 上皮性卵巢癌 ; 调节性T细胞 ; 叉头框蛋白3 ; 免疫逃逸 ; 初始T细胞 ; 细胞因子 ; 共同作用 英文关键词：CD4 T cells ; activation ; forkhead box protein 3 ; regulatory T cells ; memory T cells ; forkhead box protein 3 ; apoptosis ; epithelial ovarian carcinoma ; regulatory T cells ; forkhead box protein 3 ; immune tolerance ; na(?)ve T cells ; cytokine ; cooperative 学位年度：2010 导师：谢幸 学科代码：100211 学位授予单位：浙江大学 论文提交日期：2010-03-18 答辩委员会主席：黄荷凤

摘要

第一部分人类CD4+CD25-CD45RA+初始T细胞和CD4+CD25-CD45RA-T细胞群体有不同的FOXP3表达模式
     目的研究CD4+CD25-CD45RA+初始T细胞和CD4+CD25-CD45RA-T细胞群体静息及激活状态下叉头框蛋白3(FOXP3)的表达,以探讨不同群体细胞的可能性质及同调节性T细胞的内在联系。方法采用磁珠分选人外周血淋巴细胞,使用CD4 T细胞磁选分离试剂盒、CD25磁珠及CD45RA磁珠分离CD4+T淋巴细胞、CD4+CD25+T淋巴细胞、CD4+CD25-CD45RA+T淋巴细胞及CD4+CD25-CD45RA-T淋巴细胞,采用流式细胞仪检测其纯度,并使用流式细胞仪检测其FOXP3的表达。然后使用CD3/CD28双信号分别激活CD4+CD25-CD45RA+T淋巴细胞及CD4+CD25-CD45RA-T淋巴细胞3天,流式细胞仪检测激活后的细胞FOXP3表达。结果静息状态下的CD4+CD25-CD45RA+初始T细胞不表达FOXP3,即使使用CD3／CD28双信号激活后也很少细胞表达FOXP3,而CD4+CD25-CD45RA-T细胞在静息状态下少量细胞表达FOXP3,但是一旦激活,则高比例的细胞表达FOXP3。结论不同亚型的T细胞具有不同的FOXP3表达模式,特别是在激活状态下有明显的区别。CD4+CD25-CD45RA+T细胞在未激活时不表达FOXP3, CD3/CD28双信号刺激3天仅很少量的细胞表达FOXP3,适合作为调节性T细胞体外诱导实验的靶细胞。
     第二部分激活的人类CD4+CD25-CD45RA-T淋巴细胞高表达FOXP3并有抑制功能的体外研究
     目的研究激活后的CD4+CD25-CD45RA-T细胞的表型特征及功能,以明确激活的CD4+CD25-CD45RA-T细胞是否有调节性T细胞的抑制功能及其抑制功能的变化。方法采用磁珠分选人外周血淋巴细胞,首先采用阴性分选分离CD4+T淋巴细胞,然后使用CD25磁珠去除CD4+CD25+T淋巴细胞,而CD4+CD25-T淋巴细胞再使用CD45RA磁珠分离部分CD4+CD25-CD45RA+T淋巴细胞,剩下的细胞作为CD4+CD25-CD45RA-T细胞分别采用各种方式进行激活,激活后的细胞使用流式细胞仪检测其FOXP3的表达,然后将其同自身CD4+CD25-CD45RA+T淋巴细胞共培养,使用溴标法检测其抑制自身CD4+CD25-CD45RA+T淋巴细胞增生的能力。结果不管是否有外源性的IL-2存在,使用CD3／CD28双信号激活的CD4+CD25-CD45 RA-T细胞都有高比例的细胞表达FOXP3,而且即使是CD3单信号激活,也有高比例的细胞表达FOXP3.中和IL-10及TGF-β并不能抑制其FOXP3的表达。进一步的功能试验表明,3天激活的CD4+CD25-CD45 RA- T细胞具有抑制功能。但是随着激活时间的延长,其抑制能力减弱,抑制能力的减弱可能同大量细胞的凋亡有关。结论人类外周血记忆性T细胞群体内存在一类调节性T细胞的前体细胞,这部分细胞在静息状态下不表达FOXP3,一旦接受TCR信号的激活,特别是有合适的共刺激信号存在的条件下,则快速表达FOXP3并且具有抑制功能,但激活后有快速凋亡的特征。
     第三部分人类上皮性卵巢癌细胞诱导激活的CD4+CD25-CD45RA+初始T细胞表达FOXP3并X-有抑制功能的体外研究
     目的研究上皮性卵巢癌细胞培养上清是否能够诱导激活的CD4+CD25-CD45RA+T初始细胞表达FOXP3并具有抑制功能及其内在机制。方法采用磁珠分选的方法分离高纯度的人类CD4+CD25-CD45RA+初始T细胞,使用CD3/CD28双信号激活的方法体外激活这些细胞并且在激活的同时在培养基中加入一定比例的上皮性卵巢癌细胞培养上清,共培养3天,激活后的细胞使用流式细胞仪检测其FOXP3的表达并使用溴标法细胞共培养试验观察其抑制功能。我们也在培养系统中分别加入几种细胞因子的特异性抗体,以观察其对FOXP3表达的影响。最后我们使用细胞因子模拟或者改变卵巢癌细胞培养上清中细胞因子构成的方法观察其对FOXP3表达的影响。结果我们使用了2个上皮性卵巢癌的细胞株及5个原代培养的上皮性卵巢癌细胞,同时使用一个正常的卵巢上皮细胞培养上清作为对照。发现所有的上皮性卵巢癌细胞培养上清均能诱导激活的CD4+CD25-CD45RA+T初始细胞表达FOXP3,而正常卵巢上皮细胞培养上清没有这个能力。随后的共培养抑制试验表明这些细胞具有抑制功能。细胞因子中和试验发现中和IL-10及TGF-β及IL-4均不能抑制激活的CD4+CD25-CD45RA+T初始细胞表达FOXP3,而LIF中和抗体部分抑制其FOXP3表达,但是LIF单独并不能诱导激活后的CD4+CD25-CD45RA+T初始细胞表达FOXP3。在培养系统中加入IL-6也不影响卵巢癌细胞上清诱导的FOXP3表达。结论人类上皮性卵巢癌细胞培养上清能够诱导激活的人类CD4+CD25-CD45RA+初始T细胞表达FOXP3,并具有抑制自身免疫细胞增殖的功能,提示人类上皮性卵巢癌细胞能体外诱导非调节性T细胞转化为调节性T细胞。改变培养上清中卵巢癌细胞分泌的单一细胞因子水平,不影响人类上皮性卵巢癌细胞诱导激活的人类CD4+CD25-CD45RA+初始T细胞表达FOXP3,提示可能多种细胞因子参与了FOXP3表达的诱导,而且细胞因子间可能存在复杂的相互作用。
PARTⅠThere are different FOXP3 expression profiles of human CD4+CD25-CD45RA+T cells and CD4+CD25-CD45 RA-T cells
     Objective To study the forkhead box protein 3 (FOXP3) expression in activated or unactivated different subtypes of CD4+T cells, and to explore the latent relation between these cells and regulatory T cells.
     Methods T cells were isolated over the autoMACS Separator. CD4+ T cells, CD4+CD25+T cells, CD4+CD25-CD45RA+T cells and CD4-CD25-CD45RA-T cells were isolated with human CD4+T cell isolation kit II, CD25 microbead and CD45RA microbead respectively. The isolated T cells were cultured in complete RPMI 1640 with or without anti-CD3/CD28 dual-signal activation. The purity of all isolated populations was routinely controlled by flow cytometry. The FOXP3 expression of cultured T cells was determined by single-cell analysis using flow cvtometrv after 3 days.
     Results High purity CD4+CD25-CD45RA+ naive T cells didn't contain any cells with FOXP3 expression by single-cell analysis. Only a few of these CD4+CD25-CD45RA+T cells will express FOXP3 when they are activated with anti-CD3/CD28 dual-signal for 3 days. However, a few CD4+CD25-CD45 RA-T cells express FOXP3 without activation with anti-CD3/CD28 dual-signal, and about half of all these cells will express FOXP3 when they are activated with anti-CD3/CD28 dual-signal for 3 days. FOXP3 expression was observed in a considerable part of CD4+CD25+T cells.
     Conclusion There are different forkhead box protein 3 expression profiles in different subtypes of CD4+T cells, especially when the cells were activated with anti-CD3/CD28 dual-signal. Foxp3 expression is absent in unstimulated CD4+CD25-CD45RA+T cells, and few cells express FOXP3 in activated CD4+CD25-CD45RA+ naive T cells. The CD4+CD25-CD45RA+ naive T cells are competent precursors for the study of inducing regulatory t cells in vitro.
     PARTⅡThe activated human CD4+CD25-CD45RA-T cells express FOXP3 and exhibit suppressive ability in vitro.
     Objective To determine the suppressive ability of activated CD4+CD25-CD45RA-T cells.
     Methods The isolation and culture of T cells were shown in the part I. The FOXP3 expression of cultured T cells was determined by single-cell analysis using flow cytometry as shown in part I. The suppressive ability of activated CD4+CD25-CD45RA -T cells was determined with coculture suppression assay using a BrdU proliferation ELISA kit.
     Results More than half of CD4+CD25-CD45RA-T cells will express FOXP3 when they are activated with anti-CD3/CD28 dual-signal for 3 days in the presence or absence of exogenous IL-2. There are high rate of cells will express FOXP3 even these cells are activated just with anti-CD3 single-signal. Neutralization assays revealed that neutralizing antibody against TGF-βor interleukin-10 did not abrogate the expression of FOXP3. Furthermore, an in vitro coculture suppression assay showed that these cells could suppress the proliferation of autologous CD4+CD25-CD45RA+T cells T cells. The suppressive ability of activated CD4+CD25-CD45RA-T cells decreased accompanying with increased apoptosis as prolong of activation duration.
     Conclusion There is a subset of regulatory T cell precursors in human memory CD4+ T cells, which does not express FOXP3 in rest state, quickly express FOXP3 and exhibit suppressive ability once exposed to its cognate antigen, but experience promptly apopatosis. [Key words] regulatory T cells; memory T cells; forkhead box protein 3; apoptosis
     PART III Human epithelial ovarian carcinoma cell-derived cytokines cooperatively induce activated CD4+CD25-CD45RA+ naive T cells to express FOXP3 and exhibit suppressive ability in vitro.
     Objective To study whether the culture supernatant of human epithelial ovarian carcinoma cells could induce activated CD4+CD25-CD45RA+ naive T cells to express FOXP3 and exhibit suppressive ability in vitro and explore the involved mechanism
     Methods We collected high-purity human CD4+CD25-CD45RA+ naive T cells by microbead cell separation. The CD4+CD25-CD45RA+ naive T cells were cultured in the absence or presence of the culture supernatant of human epithelial ovarian carcinoma cells for 3 days. The FOXP3 expression of cultured T cells was determined by single-cell analysis using flow cytometry as shown in part I. The suppressive ability of induced FOXP3+ T cells was determined with coculture suppression assay using a BrdU proliferation ELISA kit. In neutralization experiments.10 ug/mL of neutralizing anti-TGF-beta. anti-IL-10, anti-IL-4, anti-LIF antibody or a combination of neutralizing anti-TGF-beta and anti-IL-10 antibody was used. In induction experiments, hrLIF or IL-6 at 10 ng/mL was used. The FOXP3 expression of cultured T cells was determined by single-cell analysis using flow cytometry as shown in part I.
     Results High-purity human CD4+CD25-CD45RA+ naive T cells did not express FOXP3 by single-cell analysis, and few cells expressed FOXP3 when they were activated with anti-CD3/CD28 dual signal. However, more cells expressed FOXP3 when the supernatant of human epithelial ovarian carcinoma cell culture was added, yet not the supernatant of normal human ovarian surface epithelia cell culture. A further coculture suppression assay showed that these cells could suppress the proliferation of autologous CD4+CD25-CD45RA-T cells. Neutralizing antibody against transforming growth factor beta (TGF-beta), interleukin-10, and interleukin-4 did not abrogate elevated FOXP3 expression induced by carcinoma cell culture supernatant, whereas neutralizing leukemia inhibitory factor (LIF) partially abrogated FOXP3 expression, but LIF alone could not increase FOXP3 expression in activated naive T cells.
     Conclusion Human epithelial ovarian carcinoma cells are able to induce expression of FOXP3 and exhibit suppressive ability in activated CD4+CD25-CD45RA+ naive T cells, which may be related with the increased regulatory T cells in the patient of ovarian carcinoma. Multiple human epithelial ovarian carcinoma cell-derived cytokines could be involved in the FOXP3 expression induction of activated CD4+CD25-CD45RA+ naive T cells. There should be a complicated interaction among these cytokines, which cooperatively induces the expression of FOXP3 in activated naive T cells and differentiates these cells into regulatory T cells.

引文

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