Coupling CD28 co-stimulation to immunoglobulin T-cell receptor molecules: The dynamics of T-cell proliferation and death
Coupling CD28 co-stimulation to immunoglobulin T-cell receptor molecules: The dynamics of T-cell proliferation and death
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DOI：
10.1097/00002371-200011000-00004
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发表时间：
2000-11-01
影响因子：
3.9
通讯作者：
Junghans, RP
中科院分区：
文献类型：
--
作者：
Beecham, EJ;Ma, QZ;Junghans, RP
免疫球蛋白T细胞受体（IgTCR）分子是潜在的有效免疫应答调节剂，因为它们允许T细胞绕过耐受。对自身抗原的耐受性一直是开发用于治疗癌症的有效过继免疫疗法的主要障碍之一。几个实验室的体外研究表明，IgTCR分子与靶抗原交联导致模型系统中的细胞溶解活性、细胞因子释放和T细胞增殖。然而，这些研究中的许多使用了已建立的T细胞系而不是正常T细胞或细胞毒性、增殖和细胞因子释放的间接测定。我们试图建立这些模型系统的有效性，同时使用正常的人T细胞开发更有效的过继免疫疗法。在本研究中，评价了IgTCR交联后T细胞增殖的活化。结果表明，除了IgTCR信号，需要CD28共刺激诱导扩增正常外周血单核细胞衍生的T细胞。单独来自IgTCR的信号可以诱导瞬时细胞分裂，但它们不诱导作为天然免疫应答特征的延长的多克隆扩增。非常强的IgTCR信号可以绕过CD28的要求，但仅在不太可能是生理相关的水平。CD28共刺激也抑制了激活诱导的细胞死亡的肿瘤反应性亚克隆的删除。这些研究证实了CD28共刺激对IgTCR修饰的人T细胞增殖的重要性，这是有效的重建抗肿瘤应答的关键特征。
Immunoglobulin T-cell receptor (IgTCR) molecules are potentially potent immune response modifiers because they allow T cells to bypass tolerance. Tolerance to self antigens has been one of the major barriers to the development of effective adoptive immunotherapies for treating cancer. In vitro studies in several laboratories have shown that cross-linking IgTCR molecules with the target antigen leads to cytolytic activity, cytokine release, and T-cell proliferation in model systems, However, many of these studies have used established T-cell lines rather than normal T cells or indirect assays of cytotoxicity, proliferation, and cytokine release. We have sought to establish the validity of these model systems while developing more effective adoptive immunotherapies using normal human T cells. In the present study the activation of T-cell proliferation after IgTCR cross-linking was evaluated. The results show that, in addition to IgTCR signals, CD28 costimulation is required to induce expansions of normal peripheral blood mononuclear cell-derived T cells. Signals from IgTCR alone can induce transient cell division, but they do not induce the prolonged polyclonal expansions that are characteristic of native immune responses. Very strong IgTCR signals could circumvent the CD28 requirement, but only at levels that are unlikely to be physiologically relevant. CD28 costimulation also suppressed the deletion of tumor-reactive subclones by activation-induced cell death. These studies confirm the importance of CD28 costimulation to thr proliferation of IgTCR-modified human T cells, a key feature of an effective, reconstructed antitumor response.