Mutis T, Cornelisse Y E, Ottenhoff T H
Department of Immunohaematology, University Hospital Leiden, The Netherlands.
Eur J Immunol. 1993 Sep;23(9):2189-95. doi: 10.1002/eji.1830230921.
Protective immunity against mycobacteria is dependent on antigen-specific T cells. Current evidence suggests that not only helper T cells that activate infected macrophages but also cytotoxic T cells (CTL) that lyse infected macrophages are involved in protection. Mycobacterium-specific CD4+ CTL are readily detectable among primary peripheral T cells but what proportion of CD4+ T cells display cytotoxic activity is not known. Whether the cytotoxic CD4+ T cells are identical to or distinct from those that produce interferon (IFN)-gamma is also unknown. In addition, studies on CTL in mycobacterial infections have focused primarily on selected antigens like hsp65 but have not analyzed systematically whether other mycobacterial antigens can activate CTL as well. These issues are relevant not only to a further understanding of protective immunity and immunopathology but also may have implications for the design of effective vaccines. To start addressing these issues, we have studied a large panel of CD4+ T cell clones specific for a broad range of mycobacterial antigens, and analyzed their ability to lyse mycobacterium-pulsed target cells and to release IFN-gamma and interleukin (IL)-4. Our results show that the vast majority of CD4+ T cell clones are able to lyse mycobacterial antigen-pulsed target cells, and that those CTL can be triggered by a wide variety of mycobacterial antigens. CD4+ CTL released high levels of IFN-gamma, but low or nondetectable levels of IL-4. In contrast, control tetanus toxoid-specific T cell clones or lines displayed poor or weak cytotoxic activity and released high levels of IL-4. The antimycobacterial clones appeared to be heterogeneous in their levels of cytotoxic activity and IFN-gamma release. Interestingly one T cell clone was able to lyse only mycobacterium-pulsed macrophages but not B cells suggesting possible selectivity in target cell recognition for some CTL. These in vitro data have to be interpreted with some caution. Nevertheless they confirm and significantly extend previous observations and suggest that mycobacteria preferentially induce CD4+ T helper type 1 (Th1)-like cells that display cytotoxic activity, and release high levels of IFN-gamma but no or little IL-4. The induction of such Th1 like cells is specific for mycobacteria since tetanus toxoid induced T cells that were poorly or not cytolytic and secreted high levels of IL-4.
针对分枝杆菌的保护性免疫依赖于抗原特异性T细胞。目前的证据表明，不仅激活被感染巨噬细胞的辅助性T细胞，而且裂解被感染巨噬细胞的细胞毒性T细胞（CTL）都参与了保护作用。在原发性外周T细胞中很容易检测到分枝杆菌特异性CD4⁺CTL，但尚不清楚有多大比例的CD4⁺T细胞具有细胞毒性活性。具有细胞毒性的CD4⁺T细胞与产生干扰素（IFN）-γ的细胞是否相同或不同也不清楚。此外，关于分枝杆菌感染中CTL的研究主要集中在如hsp65等选定抗原上，尚未系统分析其他分枝杆菌抗原是否也能激活CTL。这些问题不仅与进一步了解保护性免疫和免疫病理学相关，而且可能对有效疫苗的设计有影响。为了开始解决这些问题，我们研究了一大组针对广泛分枝杆菌抗原的CD4⁺T细胞克隆，并分析了它们裂解经分枝杆菌脉冲处理的靶细胞以及释放IFN-γ和白细胞介素（IL）-4的能力。我们的结果表明，绝大多数CD4⁺T细胞克隆能够裂解经分枝杆菌抗原脉冲处理的靶细胞，并且这些CTL可以被多种分枝杆菌抗原触发。CD4⁺CTL释放高水平的IFN-γ，但释放低水平或无法检测到的IL-4。相比之下，对照破伤风类毒素特异性T细胞克隆或细胞系表现出较弱或微弱的细胞毒性活性，并释放高水平的IL-4。抗分枝杆菌克隆在细胞毒性活性水平和IFN-γ释放方面似乎存在异质性。有趣的是，一个T细胞克隆只能裂解经分枝杆菌脉冲处理的巨噬细胞，而不能裂解B细胞，这表明某些CTL在靶细胞识别上可能具有选择性。这些体外数据必须谨慎解读。然而，它们证实并显著扩展了先前的观察结果，表明分枝杆菌优先诱导具有细胞毒性活性、释放高水平IFN-γ但不释放或仅释放少量IL-4的1型CD4⁺辅助性T（Th1）样细胞。这种Th1样细胞的诱导对分枝杆菌具有特异性，因为破伤风类毒素诱导的T细胞细胞毒性较弱或无细胞毒性，并分泌高水平的IL-4。
