Mbawuike I N, Acuna C L, Walz K C, Atmar R L, Greenberg S B, Couch R B
Department of Microbiology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Mech Ageing Dev. 1997 Mar;94(1-3):25-39. doi: 10.1016/s0047-6374(96)01855-6.
We have previously demonstrated that about 70% of elderly persons exhibit deficient cytotoxic T lymphocyte (CD8+ CTL) responses against influenza viruses when compared to young persons. Since IFN-gamma, a Th1 cytokine and IL-4, a Th2 cytokine, stimulate and inhibit CD8+ CTL responses respectively, their role(s) in the age-related CTL deficiency was investigated. Lymphocytes from young adults (34 +/- 5 years old) and elderly subjects (71 +/- 1 years old) were stimulated in vitro with influenza A/H3N2, A/H1N1 or influenza B virus for 6-7 days. The CD8+ CTL activity against virus-infected autologous target cells was significantly lower among the elderly than the young subjects (P < 0.01). Following stimulation with influenza virus, IL-4 production in both age groups was similar on day 3 but significantly higher among elderly persons on day 6 (P < 0.05). In contrast, T cells from the elderly produced significantly lower IFN-gamma than did those from young persons on both days (P < 0.05). Treatment of T cells from young and elderly adults with recombinant human IL-12, a pivotal cytokine that stimulates Th1 cytokines, resulted in enhancement of CD8+ CTL activity and IFN-gamma production in a dose dependent manner (P < 0.01). IL-12-dependent enhancement of CTL activity was not always abrogated by anti-IFN-gamma antibody treatment. These results suggest that deficient influenza virus-specific CTL activity among the elderly is attributable to a Th1 to Th2 cytokine production switch. Immunotherapy with IL-12 could represent a useful approach to correct the CD8+ CTL deficiency and cytokine imbalance among elderly humans.
我们之前已经证明，与年轻人相比，约70%的老年人对流感病毒表现出细胞毒性T淋巴细胞（CD8+ CTL）反应不足。由于Th1细胞因子IFN-γ和Th2细胞因子IL-4分别刺激和抑制CD8+ CTL反应，因此研究了它们在与年龄相关的CTL缺陷中的作用。用甲型H3N2、甲型H1N1或乙型流感病毒在体外刺激年轻成年人（34±5岁）和老年受试者（71±1岁）的淋巴细胞6-7天。老年人中针对病毒感染的自体靶细胞的CD8+ CTL活性明显低于年轻受试者（P<0.01）。用流感病毒刺激后，两组在第3天的IL-4产生相似，但在第6天老年人中的IL-4产生明显更高（P<0.05）。相反，在这两天中，老年人的T细胞产生的IFN-γ明显低于年轻人（P<0.05）。用重组人IL-12（一种刺激Th1细胞因子的关键细胞因子）处理年轻和老年成年人的T细胞，导致CD8+ CTL活性和IFN-γ产生呈剂量依赖性增强（P<0.01）。抗IFN-γ抗体处理并不总是消除IL-12依赖性的CTL活性增强。这些结果表明，老年人中流感病毒特异性CTL活性不足归因于Th1向Th2细胞因子产生的转变。用IL-12进行免疫治疗可能是纠正老年人CD8+ CTL缺陷和细胞因子失衡的一种有用方法。
