SHIV感染中国恒河猴外周血Th17细胞变化趋势的研究
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摘要
目前,艾滋病已成为影响人类健康的最严重的传染性疾病之一,CD4+T细胞大量损耗是HIV病毒感染的主要特征之一。传统的CD4+T细胞分为以分泌IFNγ为主的Th1细胞及以分泌IL-4为主的Th2细胞两个亚群。Th17细胞是新近发现与Th1和Th2平行的一类CD4+辅助性T细胞,主要分泌IL-17和IL-22,是粘膜屏障的重要组成部分,在自身免疫病、炎症和感染免疫中发挥重要作用。
本文利用CCR5嗜性的人猴嵌合病毒SHIV-SF162P4,通过静脉注射和多次低剂量粘膜接种两种方式,分别在8只和4只中国恒河猴中建立稳定感染。运用胞内细胞因子染色和流式细胞分析技术,研究感染后外周血淋巴细胞中CD4+T细胞各个亚群：Th1、Th2、Th17及调节性T细胞所占比例的变化趋势及各群间相对大小的动态变化,分析这些变化与病毒载量、CD4+T细胞计数和CD4+记忆T细胞水平等疾病进程重要指标之间的相关性。同时,根据各个细胞亚群分化相关核转录调控分子和细胞因子的核苷酸序列设计Taqman探针,建立了Real-time RT-PCR定量分析技术,检测了IL-17、RORγt、GATA-3、T-bet、TGFβ及Foxp3等基因mRNA表达水平在SHIV感染后的变化趋势。
研究发现,在急性感染期,随着疾病进程,静脉注射病毒组Th17细胞检出频率变化与血浆病毒载量变化呈负相关；静脉注射病毒组和粘膜接种病毒组IL-17+细胞与Foxp3+细胞在CD4+T细胞中的比例呈现先升后降的趋势,并与病毒载量变化成正相关；静脉注射病毒组IL-17+细胞与Foxp3+细胞在CD4+T细胞中的比例变化与CD4+记忆细胞在淋巴细胞中的比例变化趋势呈正相关；与Th17和Treg细胞分化相关的核转录调控因子RORγt、Foxp3在mRNA水平的比值,也与病毒载量变化趋势成正相关。通过以上分析,证明Th17细胞在CD4+T细胞中的检出频率、Th17与Treg之间的动态平衡与AIDS疾病进程有关。
CCR5嗜性SHIV在AIDS病理、免疫和疫苗研究中得已广泛应用,在粘膜感染,免疫保护机制等方面可能更贴近HIV感染。本文首次利用CCR5嗜性SHIV感染中国恒河猴为动物模型,研究了急性感染期Th17等CD4+辅助性T细胞各亚群及Treg亚群的频率以及各个亚群相对平衡的动态变化趋势,阐述了它们各自变化趋势与疾病进程的关系,为揭示Th17和Treg等辅助性T细胞亚群在HIV感染和AIDS病理过程中的作用和机制提供了重要的第一手资料
AIDS(Acquired Immunodeficiency Syndrome), caused by Human Immunodeficiency Virus (HIV) infection, has become the leading fatal infectious disease threatening human health. One of the most significant symptoms in HIV infection is the great loss of CD4+ T lymphocytes. Classically, CD4+ T helper cell is divided into two subtypes: IFNy secreting T helper 1 cells and IL-4 secreting T helper 2 cells. As a newly demonstrated subpopulation of T helper cell, IL-17 and IL-22 secreting Th17 cells play a critical role in autoimmune disease, inflammation and infectious immunology. In this research, eight Chinese-origin rhesus macaques were inoculated intravenously with SHIV-sfl62p4 while the other four were exposed to 10 low-dose SHIV-sfl62p4 to construct stable SHIV infection. Intracellular cytokines staining and Flow Cytometry were used to evaluate the levels of different CD4+ T helper subpopulations and their balance pre-and-post infection. Besides, the correlation between these levels and viral load or the frequency of CD4+ T memory cells respectively, which have been associated with AIDS progression, were also analysed. Referring to sequences of nuclear transcriptional regulatory factors and cytokines which regulated the differentiation of these different CD4+ T cell subpopulations, primers and Taqman probes for real time RT-PCR assay were designed, the level and tendency of mRNA level of these factors pre and post infection were examined.
According to our data, in acute phase of infection, the correlation between Th17 frequency and viral load was significant in i.v. challenge group; the ratio of IL-17+ cells over Foxp3+ cells, which decreased in the first few weeks and increased later, was negatively correlated to viral load, both in intravenously inoculated group and rectum exposed group. The ratio in intravenously inoculated group also has significant positive correlation to the frequency of CD4+ T memory cell. Besides, the ratio of RORyt and Foxp3 on transcriptional level is also correlated to viral load. CCR5-tropism SHIV have been extensively used in AIDS research, we are the first to use CCR5-tropism SHIV infected Chinese rhesus macaques to investigate the dynamics of both different CD4+ T helper subpopulations and their balance after SHIV infection. Besides, the correlations between these changes and disease progression were also elucidated. It provided important data for understanding the role and mechanism of Th17 in the acute phase of HIV infection
本文利用CCR5嗜性的人猴嵌合病毒SHIV-SF162P4,通过静脉注射和多次低剂量粘膜接种两种方式,分别在8只和4只中国恒河猴中建立稳定感染。运用胞内细胞因子染色和流式细胞分析技术,研究感染后外周血淋巴细胞中CD4+T细胞各个亚群：Th1、Th2、Th17及调节性T细胞所占比例的变化趋势及各群间相对大小的动态变化,分析这些变化与病毒载量、CD4+T细胞计数和CD4+记忆T细胞水平等疾病进程重要指标之间的相关性。同时,根据各个细胞亚群分化相关核转录调控分子和细胞因子的核苷酸序列设计Taqman探针,建立了Real-time RT-PCR定量分析技术,检测了IL-17、RORγt、GATA-3、T-bet、TGFβ及Foxp3等基因mRNA表达水平在SHIV感染后的变化趋势。
研究发现,在急性感染期,随着疾病进程,静脉注射病毒组Th17细胞检出频率变化与血浆病毒载量变化呈负相关；静脉注射病毒组和粘膜接种病毒组IL-17+细胞与Foxp3+细胞在CD4+T细胞中的比例呈现先升后降的趋势,并与病毒载量变化成正相关；静脉注射病毒组IL-17+细胞与Foxp3+细胞在CD4+T细胞中的比例变化与CD4+记忆细胞在淋巴细胞中的比例变化趋势呈正相关；与Th17和Treg细胞分化相关的核转录调控因子RORγt、Foxp3在mRNA水平的比值,也与病毒载量变化趋势成正相关。通过以上分析,证明Th17细胞在CD4+T细胞中的检出频率、Th17与Treg之间的动态平衡与AIDS疾病进程有关。
CCR5嗜性SHIV在AIDS病理、免疫和疫苗研究中得已广泛应用,在粘膜感染,免疫保护机制等方面可能更贴近HIV感染。本文首次利用CCR5嗜性SHIV感染中国恒河猴为动物模型,研究了急性感染期Th17等CD4+辅助性T细胞各亚群及Treg亚群的频率以及各个亚群相对平衡的动态变化趋势,阐述了它们各自变化趋势与疾病进程的关系,为揭示Th17和Treg等辅助性T细胞亚群在HIV感染和AIDS病理过程中的作用和机制提供了重要的第一手资料
AIDS(Acquired Immunodeficiency Syndrome), caused by Human Immunodeficiency Virus (HIV) infection, has become the leading fatal infectious disease threatening human health. One of the most significant symptoms in HIV infection is the great loss of CD4+ T lymphocytes. Classically, CD4+ T helper cell is divided into two subtypes: IFNy secreting T helper 1 cells and IL-4 secreting T helper 2 cells. As a newly demonstrated subpopulation of T helper cell, IL-17 and IL-22 secreting Th17 cells play a critical role in autoimmune disease, inflammation and infectious immunology. In this research, eight Chinese-origin rhesus macaques were inoculated intravenously with SHIV-sfl62p4 while the other four were exposed to 10 low-dose SHIV-sfl62p4 to construct stable SHIV infection. Intracellular cytokines staining and Flow Cytometry were used to evaluate the levels of different CD4+ T helper subpopulations and their balance pre-and-post infection. Besides, the correlation between these levels and viral load or the frequency of CD4+ T memory cells respectively, which have been associated with AIDS progression, were also analysed. Referring to sequences of nuclear transcriptional regulatory factors and cytokines which regulated the differentiation of these different CD4+ T cell subpopulations, primers and Taqman probes for real time RT-PCR assay were designed, the level and tendency of mRNA level of these factors pre and post infection were examined.
According to our data, in acute phase of infection, the correlation between Th17 frequency and viral load was significant in i.v. challenge group; the ratio of IL-17+ cells over Foxp3+ cells, which decreased in the first few weeks and increased later, was negatively correlated to viral load, both in intravenously inoculated group and rectum exposed group. The ratio in intravenously inoculated group also has significant positive correlation to the frequency of CD4+ T memory cell. Besides, the ratio of RORyt and Foxp3 on transcriptional level is also correlated to viral load. CCR5-tropism SHIV have been extensively used in AIDS research, we are the first to use CCR5-tropism SHIV infected Chinese rhesus macaques to investigate the dynamics of both different CD4+ T helper subpopulations and their balance after SHIV infection. Besides, the correlations between these changes and disease progression were also elucidated. It provided important data for understanding the role and mechanism of Th17 in the acute phase of HIV infection
引文
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