«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《传染病信息》[ISSN:1007-8134/CN:11-3886/R]

期数:

2019年02期

页码:

113-118

栏目:

论 著

出版日期:

2019-05-15

文章信息/Info

Title:

Plasma exosomes immune-regutalion role on CD8+ T cells and its relationship with CD4/CD8 ratio in HIV-infected cART-treated complete responder

文章编号:

1007-8134(2019)02-0113-06

作者:

杨　涛; 周明菊; 李华杰; 黄辉煌; 徐若男; 施　明

100039 北京，中国人民解放军总医院第五医学中心感染性疾病诊疗与研究中心（杨涛、周明菊、李华杰、黄辉煌、徐若男、施明）

Author(s):

YANG Tao;  ZHOU Ming-ju;  LI Hua-jie;  HUANG Hui-huang;  XU Ruo-nan;  SHI Ming*

Treatment and Research Center for Infectious Diseases, the Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China

关键词:

人类免疫缺陷病毒-1; CD4/CD8 比值; 外泌体; T 细胞

Keywords:

HIV-1;  CD4/CD8 ratio;  exosomes;  T cells

分类号:

R512.91

DOI:

10.3969/j.issn.1007-8134.2019.02.004

文献标识码:

A

摘要:

目的　探究HIV-1 慢性感染者长期联合抗反转录病毒治疗（combination antiretroviral therapy, cART）后血浆 中外泌体的特点，分析其动态变化与患者CD4/CD8 比值的关系，并探讨其对CD8+ T 细胞的潜在免疫调节作用。方法　入 组cART 后完全应答（complete respond, CR）患者19 例，根据患者CD4/CD8 比值分为异常组（CD4/CD8 ＜ 0.8）10 例和 复常组（CD4/CD8 ＞ 0.8）9 例，设立健康对照（healthy control, HC）5 例。比较3 组患者血浆外泌体的浓度，通过体外 功能实验观察外泌体对CD8+ T 细胞活化水平、分泌细胞因子能力和增殖能力的影响，分析其与CD4/CD8 比值的关系。 结果　异常组血浆外泌体浓度显著高于复常组和HC 组，且CR 患者外泌体的浓度与CD4/CD8 比值呈负相关（r =-0.648， P=0.043）。异常组外泌体抑制CD8+ T 细胞活化指标CD38+HLA-DR+ 的共表达，且抑制效果与患者CD4/CD8 比值相关（r=0.478， P=0.039）；异常组血浆外泌体抑制CD8+ T 细胞分泌IFN-γ 和IL-2 ，且抑制效果与患者的CD4/CD8 比值显著相关（r=0.654， P=0.002；r=0.700，P ＜ 0.001）；异常组患者血浆外泌体能够抑制CD8+ T 细胞的增殖，且抑制效果与患者CD4/CD8 比值 显著相关（r=0.716，P ＜ 0.001）。结论　CD4/CD8 比值异常患者外泌体能抑制CD8+ T 细胞的活化、增殖及分泌， 提示CD4/CD8 比值异常的CR 患者体内升高的外泌体对机体过度的免疫活化和炎症状态具有抑制作用。　

Abstract:

Objective　To investigate the characteristics of plasma exosomes in chronically HIV-infected patients who received long-term combination antiretroviral therapy (cART), to analyze the relationship between dynamic changes of plasma exosomes and CD4/ CD8 ratio, and to explore the potential immune-regulation role of plasma exosomes on CD8+ T cells. Methods　Nineteen complete responders (CR) received cART were enrolled and divided into abnormal group (CD4/CD8 ＜ 0.8, n=10) and normalized group (CD4/CD8 ＞ 0.8, n=9) according to the CD4/CD8 ratio. Five healthy controls (HC) were also enrolled. The concentrations of plasma exosomes in 3 groups (n=5 per group) were compared, the effects of plasma exosomes on the activation, cytokine secretion and proliferation on CD8+ T cells were investigated through in vitro functional experiment. The relationship between plasma exosomes and CD4/CD8 ratio was analyzed. Results　The concentration of plasma exosomes in abnormal group was significantly higher than that in normalized group and the HC group, and negatively correlated with the CD4/CD8 ratio in CRs (r=-0.648, P=0.043). Plasma exosomes in abnormal group inhibited the co-expression of CD38HLA-DR+, an indicator of activation of CD8+ T cells, and the inhibitory effect was correlated with the CD4/CD8 ratio in CRs (r=0.478, P=0.039). Plasma exosomes in abnormal group inhibited the secretion of IFN-γ and IL-2 in CD8+ T cells, and the inhibitory effect was significantly correlated with the CD4/CD8 ratio in CRs (r=0.654, P=0.002; r=0.700, P ＜ 0.001). Plasma exosomes in abnormal group inhibited the proliferation of CD8+ T cells, and there was a significant correlation between the inhibitory effect and the CD4/CD8 ratio in CRs (r=0.716, P＜ 0.001). Conclusions　Plasma exosomes from CD4/CD8 abnormal patients inhibites the activation, secretion and proliferation of CD8+ T cells, suggesting that elevated exosomes in CRs with abnormal CD4/CD8 ratio has an inhibitory effect on over-activation and excessive inflammation in HIV patients.

参考文献/References

[1] Freiberg MS, Chang CCH, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction［J］. JAMA Intern Med, 2013, 173(8):614-622.
[2] Appay V, Sauce D. Immune activation and inflammation in HIV- 1 infection: causes and consequences［J］. J Pathol, 2008, 214(2):231-241.
[3] Serrano-Villar S, Gutiérrez C, Vallejo A, et al. The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression［J］. J Infect, 2013, 66(1):57-66.
[4] Tinago W, Coghlan E, Macken A, et al. Clinical, immunological and treatment-related factors associated with normalised CD4+/ CD8+ T-cell ratio: effect of na?ve and memory T-cell subsets［J］. PLoS One, 2014, 9(5):e97011.
[5] Buggert M, Frederiksen J, Noyan K, et al. Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection［J］. J Immunol, 2014, 192(5):2099-2108.
[6] Serrano-Villar S, Sainz T, Lee SA, et al. HIV-infected individuals with low CD4/CD8 ratio despite effective antiretroviral therapy exhibit altered T cell subsets, heightened CD8+ T cell activation, and increased risk of non-AIDS morbidity and mortality［J］. PLoS Pathog, 2014, 10(5):e1004078.
[7] Mussini C, Lorenzini P, Cozzi-Lepri A, et al. CD4/CD8 ratio normalisation and non-AIDS-related events in individuals with HIV who achieve viral load suppression with antiretroviral therapy: an observational cohort study［J］. Lancet HIV, 2015,2(3):e98-e106.
[8] Shenoda BB, Ajit SK. Modulation of immune responses by exosomes derived from antigen-presenting cells［J］. Clin Med Insights Pathol, 2016, 9(Suppl 1):S1-S8.
[9] Chaput N, Clotilde Théry. Exosomes: immune properties and potential clinical implementations［J］. Semin Immunopathol, 2011, 33(5):419-440.
[10] Skog J, Würdinger T, Van Rijn S, et al. Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers［J］. Nat Cell Biol, 2008, 10(12):1470- 1476.
[11] Théry C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses［J］. Nat Rev Immunol, 2009, 9(8):581- 593.
[12] Meckes DG, Raabtraub N. Microvesicles and viral infection［J］. J Virol, 2011, 85(25):12844-12854.
[13] Carvalho JVD, Castro ROD, Silva EZMD, et al. Nef neutralizes the ability of exosomes from CD4+ T cells to act as decoys during HIV- 1 infection［J］. PLoS One, 2014, 9(11):e113691.
[14] Duette G, Pereyra GP, Rubione J, et al. Induction of HIF-1α by HIV-1 infection in CD4+ T cells promotes viral replication and drives extracellular vesicle-mediated inflammation［J］. MBio, 2018, 9(5):pii:e00757-18.
[15] Giri PK, Schorey JS. Exosomes derived from M. Bovis BCG infected macrophages activate antigen-specific CD4+ and CD8+ T cells in vitro and in vivo［J］. PLoS One, 2008, 3(6):e2461.
[16] Lugini L, Cecchetti S, Huber V, et al. Immune surveillance properties of human NK cell-derived exosomes［J］. J Immunol, 2012, 189(6):2833-2842.
[17] Xie Y, Zhang H, Li W, et al. Dendritic cells recruit T cell exosomes via exosomal LFA-1 leading to inhibition of CD8+ CTL responses through downregulation of peptide/MHC class I and Fas ligandmediated cytotoxicity［J］. J Immunol, 2010, 185(9):5268-5278.
[18] 中华医学会感染病学分会艾滋病丙型肝炎学组，中国疾病预 防与控制中心. 中国艾滋病诊疗指南（2018 版）［J］. 传染 病信息，2018，31(6):481-499，504.
[19] Gang C, Xiaowei X, Wei G, et al. Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response［J］. Nature, 2018, 560(7718):382-386.
[20] Sonja L, Theofanis F, Theresa L, et al. Suppression of lymphocyte functions by plasma exosomes correlates with disease activity in patients with head and neck cancer［J］. Clin Cancer Res, 2017, 23(16):4843-4854.
[21] Okoye I, Coomes S, Pelly V, et al. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells［J］. Immunity, 2014, 41(1):89-103.
[22] Tung SL, Boardman DA, Sen M, et al. Regulatory T cell-derived extracellular vesicles modify dendritic cell function［J］. Sci Rep, 2018, 8(1):6065.

备注/Memo

备注/Memo:

[ 基金项目]　“十三五”国家传染病重大专项（2018ZX10302104-002）
[ 通信作者]　施明，E-mail: shiming302@sina.com
*Corresponding author, E-mail: shiming302@sina.com

常用功能

更新日期/Last Update: 2019-05-15