CD28 ACTIVATION PROMOTES TH2 SUBSET DIFFERENTIATION BY HUMAN CD4(+) CELLS
CD28 ACTIVATION PROMOTES TH2 SUBSET DIFFERENTIATION BY HUMAN CD4(+) CELLS
复制标题
DOI：
10.1002/eji.1830250242
复制
发表时间：
1995-02-01
影响因子：
5.4
通讯作者：
THYPHRONITIS, G
中科院分区：
文献类型：
--
作者：
KING, CL;STUPI, RJ;THYPHRONITIS, G
CD 28的连接为T细胞活化提供了必要的共刺激信号，导致体外白细胞介素（IL）-2的产生增加，但其在IL-4和其他细胞因子的产生以及辅助性T细胞（Th）的功能分化中的作用仍不确定。我们研究了高纯度成人和新生儿CD 4（+）T细胞的细胞因子的生产模式与抗CD 3，佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）和离子霉素，或植物血凝素（PHA）在存在或不存在的抗CD 28在重复刺激休息周期激活。与单独用抗CD 3或促分裂原刺激的细胞相比，用抗CD 3（或促分裂原PHA或PMA+离子霉素）和抗CD 28单克隆抗体初始刺激CD 4（+）细胞诱导IL-4、IL-5和干扰素-γ（IFN-γ）产生，并增加IL-2产生（6- 11倍）。抗CD 28诱导的细胞因子产生与IL-4和IL-5 mRNA水平增加相对应，表明基因表达和/或mRNA稳定性增加。然而，最引人注目的是，随着CD 28刺激的重复连续循环，IL-4和IL-5的产生逐渐增强，IL-2和LFN-gamma的产生减少。增强的Th 2样应答与IL-4分泌细胞的频率增加相关;在第三轮刺激时，高达70%的细胞产生IL-4，相比之下，如通过ELISPOT测定的，在第一次刺激后仅5%。CD 28活化还促进了幼稚新生儿CD 4（+）细胞中的Th 2反应，表明Th细胞被诱导表达Th 2反应，而不是优先扩增已经建立的Th 2型细胞。这种CD 28介导的应答是IL-4非依赖性的，因为在存在中和性抗IL-4抗体的情况下，通过重复刺激循环增强的IL-5产生不受影响。这些结果表明，CD 28活化可能在人类Th 2亚群的分化中发挥重要作用。
Ligation of CD28 provides a costimulatory signal to T cells necessary for their activation resulting in increased interleukin (IL)-2 production in vitro, but its role in IL-4 and other cytokine production and functional differentiation of T helper (Th) cells remains uncertain. We studied the pattern of cytokine production by highly purified human adult and neonatal CD4(+) T cells activated with anti-CD3, phorbol 12-myristate 13-acetate (PMA) and ionomycin, or phytohemagglutinin (PHA) in the presence or absence of anti-CD28 in repetitive stimulation-rest cycles. Initial stimulation of CD4(+) cells with anti-CD3 (or the mitogens PHA or PMA+ionomycin) and anti-CD28 monoclonal antibodies induced IL-4, IL-5 and interferon-gamma (IFN-gamma) production and augmented IL-2 production (6- to 11-fold) compared to cells stimulated with anti-CD3 or mitogen alone. The anti-CD28-induced cytokine production corresponded with augmented IL-4 and IL-5 mRNA levels suggesting increased gene expression and/or mRNA stabilization. Most striking, however, was the progressively enhanced IL-4 and IL-5 production and diminished IL-2 and LFN-gamma production with repetitive consecutive cycles of CD28 stimulation. The enhanced Th2-like response correlated with an increased frequency of IL-4-secreting cells; up to 70 % of the cells produced IL-4 on the third round of stimulation compared to only 5 % after the first stimulation as determined by ELISPOT. CD28 activation also promoted a Th2 response in naive neonatal CD4(+) cells, indicating that Th cells are induced to express a Th2 response rather than preferential expansion of already established Th2-type cells. This CD28-mediated response was IL-4 independent, since enhanced IL-5 production with repetitive stimulation cycles was not affected in the presence of neutralizing anti-IL-4 antibodies. These results indicate that CD28 activation may play an important role in the differentiation of the Th2 subset in humans.