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）感染的特征是CD 4 + T细胞的不可阻挡的下降。CD 4 + T细胞在许多病毒感染中维持记忆性细胞毒性T细胞（CTL）应答中起重要作用。最近，在小鼠模型中，已经证明CD 4 + T细胞通过CD 40配体-CD 40相互作用来帮助CTL应答。该项目研究了CD 4 + T细胞和CD 40配体在正常人类志愿者和HIV-1感染者中产生有效记忆细胞毒性T细胞（CTL）反应的作用。我们已经证明，在2/2的HIV-1未感染受试者中，CD 4的帮助是针对流感病毒的最佳体外CTL应答所必需的。加入CD 40-配体显著增强了CTL应答，并且能够在2/2的HIV-1未感染受试者中完全补偿CD 4耗竭条件下的CD 4帮助。在HIV-1感染者中，5/6例患者的最佳HIV-1特异性体外CTL应答需要CD 4的帮助。在一个长期的非进展患者中，最佳的CTL应答可以在没有CD 4帮助的情况下在体外诱导。5/6例HIV-1感染者CD 40- ligand可增强CTL应答，但3/6例患者CD 40- ligand不能完全替代CD 4辅助。在大多数患者中，外源性细胞因子如IL-2、IL-12或IL-15的添加能够替代CD 4 T细胞的帮助。因此，我们的研究结果表明，在诱导有效的记忆性抗病毒CTL反应的CD 4辅助和CD 40配体的重要性。我们无法 救援 在3/6例HIV-1感染患者中，CD 4帮助CD 40配体，表明这些患者中存在CD 8细胞的内在缺陷，需要进一步研究。- CD 4辅助;细胞毒性T细胞反应;人类免疫缺陷病毒-1;人体组织; CD 40配体; CD 8四聚体。

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.