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

CD4 T 细胞帮助和 CD40 配体在抗 HIV-1 细胞毒性 T 细胞反应中的作用

• 批准号: 6431718
• 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/6431718
• 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. This project examined 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. CD4 help was required for optimal in-vitro CTL responses against influenza in normal subjects. CD40 ligand enhanced CTL responses and was able to completely substitute for CD4 help in these normal subjects in vitro. In HIV-1 infected individuals, CD4 help was required for optimal HIV-1-specifc in-vitro CTL responses in 9/10 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 most HIV-1 infected patients; however, CD40 ligand could not completely replace CD4 help in some patients. The mechanism of poor responsiveness to CD40 ligand was shown to involve dysfunction of circulating CD8+ memory T cells, which could be corrected by addition of cytokines such as interleukin-2. In addition, interleukin-15 produced by CD40LT-stimulated dendritic cells may be an additional mediator of CD40LT-induced expansion of memory CTL responses. Our findings demonstrate the importance of CD4 help and CD40 ligand in inducing effective memory anti-viral CTL responses, and suggest that some HIV-infected patients have an intrinsic defect of CD8+ T cells.

人类免疫缺陷病毒（HIV-1）感染的特征是CD4 + T细胞无法下降。已经显示，CD4+ T细胞在许多病毒感染中维持记忆细胞毒性T细胞（CTL）反应中起着重要作用。 最近，在小鼠模型中，已经证明CD4 + T细胞通过CD40配体CD40相互作用帮助CTL响应。 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感染个体中产生有效记忆细胞毒性T细胞（CTL）反应中的作用。 在正常受试者中，对针对流感的最佳体外CTL反应需要CD4帮助。 CD40配体增强了CTL反应，并能够在体外这些正常受试者中完全代替CD4帮助。 在HIV-1感染的个体中，9/10例患者中最佳的HIV-1-specifc内外CTL反应需要CD4帮助。 在一个长期的非促进患者中，无需CD4帮助就可以在体外诱导最佳CTL反应。 CD40配体可以增强大多数HIV-1感染患者的CTL反应；但是，在某些患者中，CD40配体无法完全取代CD4帮助。 证明对CD40配体反应不良的机制涉及循环CD8+记忆T细胞功能障碍，可以通过添加细胞因子（例如白介素2）来纠正。 此外，由CD40LT刺激的树突状细胞产生的白介素15可能是CD40LT诱导的存储器CTL响应扩展的附加介体。 我们的发现表明，CD4帮助和CD40配体在诱导有效记忆抗病毒CTL反应中的重要性，并表明某些HIV感染的患者具有CD8+ T细胞的固有缺陷。