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

人类免疫缺陷病毒(HIV-1)感染的特点是CD4+T细胞不可阻挡地下降。已有研究表明，在多种病毒感染中，CD4+T细胞在维持记忆细胞毒性T细胞(CTL)反应中起重要作用。最近，在小鼠模型中，已经证明CD4+T细胞通过CD40配体-CD40相互作用来帮助CTL反应。该项目研究了在正常人和HIV-1感染者中，CD4+T细胞和CD40配体在产生有效的记忆细胞毒性T细胞(CTL)反应中的作用。在正常受试者中，针对流感的最佳体外CTL反应需要CD4帮助。在体外，CD40配体可增强CTL反应，并能完全替代这些正常受试者的CD4-Help。在HIV-1感染者中，需要CD4帮助才能在9/10的患者中获得最佳的HIV-1特异性体外CTL反应。在一名长期无进展的患者中，在没有CD4帮助的情况下，体外可以诱导出最佳的CTL反应。CD40配体可增强大多数HIV-1感染者的CTL应答，但CD40配体并不能完全替代部分患者的CD4帮助。对CD40配体反应性差的机制被证明与循环CD8+记忆T细胞功能障碍有关，这种功能障碍可以通过添加细胞因子如白介素2来纠正。此外，CD40LT刺激的树突状细胞产生的IL-15可能是CD40LT诱导的记忆性CTL反应扩大的额外介质。我们的发现证明了CD4帮助和CD40配体在诱导有效的记忆性抗病毒CTL反应中的重要性，并提示一些HIV感染患者存在CD8+T细胞的固有缺陷。

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.