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

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。我们已经证明，在2/2未感染HIV-1的受试者中，需要CD4帮助才能在体外对流感产生最佳的CTL反应。CD40-Ligand的加入极大地增强了CTL反应，并能够在2/2未感染HIV-1的受试者中完全补偿CD4耗尽条件下的CD4帮助。在HIV-1感染者中，需要CD4帮助才能在5/6的患者中获得最佳的HIV-1特异性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5/6例HIV-1感染者的CTL应答，但CD40配体不能完全替代3/6例HIV-1感染者。在大多数患者中，外源性细胞因子如IL-2、IL-12或IL-15的加入能够替代CD4T细胞的帮助。因此，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。我们不能用CD40配体在3/6的HIV-1感染患者中挽救CD4帮助，这表明这些患者的CD8细胞存在内在缺陷，这将值得进一步研究。-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。

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.