The Role of CD4 T cell Help and CD40 Ligand in anti-HIV-1 Cytotoxic CD8 T cell

CD4 T 细胞帮助和 CD40 配体在抗 HIV-1 细胞毒性 CD8 T 细胞中的作用

• 批准号: 6227853
• 负责人: Mario Ostrowski
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6227853
• 关键词: CD40 molecule; HIV infections; cell cell interaction; cellular immunity; cytotoxic T lymphocyte; helper T lymphocyte; human immunodeficiency virus 1; interleukin 12; interleukin 15; interleukin 2; laboratory mouse

Human immunodeficiency virus (HIV-1) infection is characterized by an inexorable decline in CD4 + T cells. CD4+ T cells have been shown play an important role in maintaining memory cytotoxic T cell (CTL) responses in a number of viral infections. Recently, in mouse models, it has been demonstrated that CD4 + T cells help CTL responses via CD40 ligand-CD40 interactions. The project examines the role of CD4+ T cells and CD40 ligand in producing an effective memory cytotoxic T cell (CTL) response in both normal human volunteers and HIV-1 infected individuals. We have demonstrated that CD4 help is required for optimal in-vitro CTL responses against influenza in 2/2 HIV-1 uninfected subjects. The addition of CD40-Ligand dramatically enhanced CTL responses and was able to completely compensate for CD4 help in CD4- depleted conditions in 2/2 HIV-1 uninfected subjects. In HIV-1 infected individuals, CD4 help was required for optimal HIV-1-specifc in-vitro CTL responses in 5/6 patients. In one long term non-progressor patient, optimal CTL responses could be induced in-vitro without CD4 help. CD40- ligand could enhance CTL responses in 5/6 HIV-1 infected patients, however, CD40 ligand could not completely replace CD4 help in 3/6 patients. The addition of exogenous cytokines such as IL-2, IL-12 or IL-15 was able to substitute for CD4 T cell help in most patients. Thus our findings demonstrate the importance of CD4 help and CD40 ligand in inducing effective memory anti-viral CTL responses. Our inability to rescue CD4 help with CD40 ligand in 3/6 HIV-1 infected patients suggests an intrinsic defect of CD8 cells in these patients that will warrant further study. - CD4 help; cytotoxic T cell response; human immunodeficiency virus-1; human tissues; CD40 ligand; CD8 tetramer.

人类免疫缺陷病毒 (HIV-1) 感染的特点是 CD4 + T 细胞不可避免地下降。 CD4+ T 细胞已被证明在维持许多病毒感染中的记忆细胞毒性 T 细胞 (CTL) 反应中发挥着重要作用。最近，在小鼠模型中，已证明 CD4 + T 细胞通过 CD40 配体-CD40 相互作用帮助 CTL 应答。该项目研究了 CD4+ T 细胞和 CD40 配体在正常人类志愿者和 HIV-1 感染者中产生有效的记忆细胞毒性 T 细胞 (CTL) 反应中的作用。我们已经证明，在 2/2 HIV-1 未感染受试者中，CD4 的帮助是针对流感的最佳体外 CTL 反应所必需的。 CD40-配体的添加显着增强了CTL反应，并且能够完全补偿2/2 HIV-1未感染受试者中CD4耗尽条件下的CD4帮助。在 HIV-1 感染者中，5/6 的患者需要 CD4 的帮助才能获得最佳的 HIV-1 特异性体外 CTL 反应。在一名长期无进展的患者中，无需 CD4 的帮助即可在体外诱导最佳 CTL 反应。 CD40-配体可以增强5/6 HIV-1感染患者的CTL应答，然而，CD40配体不能完全替代CD4对3/6患者的帮助。在大多数患者中，添加外源细胞因子（例如 IL-2、IL-12 或 IL-15）能够替代 CD4 T 细胞的帮助。因此，我们的研究结果证明了 CD4 帮助和 CD40 配体在诱导有效的记忆抗病毒 CTL 反应中的重要性。我们无法在 3/6 HIV-1 感染患者中用 CD40 配体挽救 CD4 帮助，这表明这些患者的 CD8 细胞存在内在缺陷，需要进一步研究。 - CD4帮助；细胞毒性T细胞反应；人类免疫缺陷病毒-1；人体组织； CD40配体； CD8四聚体。