Wang M H, Chen Y Q, Gercken J, Ernst M, Böhle A, Flad H D, Ulmer A J
Department of Immunology and Cell Biology, Forschungsinstitut Borstel, Germany.
Scand J Immunol. 1993 Sep;38(3):239-46. doi: 10.1111/j.1365-3083.1993.tb01720.x.
Tumour regression induced in cancer patients by local instillation of Bacillus Calmette-Guérin (BCG) into the bladder has been considered to be mainly mediated by activated cellular immunity and inflammatory reactions. In the present study we investigated the cytotoxicity of T cells bearing gamma/delta T-cell receptors (gamma/delta + cells) against bladder carcinoma cells in vitro. Long-term cultured gamma/delta + T-cell lines from peripheral blood lymphocytes of healthy donors were established by stimulation with sonicated cell wall-associated antigens of Mycobacterium tuberculosis (SMA). These gamma/delta + T cells lack the natural killer (NK) markers CD16 and CD56, as determined by flow cytometry. The SMA-specific gamma/delta + T cells exhibited profound cytotoxicity against two NK-resistant bladder tumour cell lines as well as against NK-sensitive tumour cells in a non-major histocompatibility complex-restricted manner. The pattern of tumour cells killed by gamma/delta + T cells differed significantly from those of NK cells and lymphokine-activated killer LAK cells. Furthermore, we tested the effects of recombinant human cytokines, including interleukin (IL)-1, IL-2, IL-4, IL-6, interferon (IFN)-gamma and tumour necrosis factor (TNF), on gamma/delta + T-cell-mediated cytotoxicity. It was shown that the addition of recombinant TNF in co-incubation could augment gamma/delta + T-cell-mediated killing of two bladder tumour cell lines, but not of cells of the erythroleukaemia cell line K562. Based on these results it was concluded that mycobacterial antigens could specifically activate resting gamma/delta + T cells. The cytotoxicity of gamma/delta + T cells against bladder tumour cells and its selective enhancement by TNF may be an important mechanism involved in bladder tumour regression induced by intravesical instillation of BCG.
通过向膀胱内局部滴注卡介苗（BCG）诱导癌症患者肿瘤消退，这一过程被认为主要由激活的细胞免疫和炎症反应介导。在本研究中，我们体外研究了携带γ/δ T细胞受体的T细胞（γ/δ +细胞）对膀胱癌细胞的细胞毒性。通过用结核分枝杆菌的超声处理的细胞壁相关抗原（SMA）刺激，从健康供体的外周血淋巴细胞建立了长期培养的γ/δ + T细胞系。通过流式细胞术测定，这些γ/δ + T细胞缺乏自然杀伤（NK）标志物CD16和CD56。SMA特异性γ/δ + T细胞以非主要组织相容性复合体限制的方式，对两种NK抗性膀胱肿瘤细胞系以及NK敏感肿瘤细胞表现出显著的细胞毒性。γ/δ + T细胞杀死的肿瘤细胞模式与NK细胞和淋巴因子激活的杀伤性LAK细胞的模式有显著差异。此外，我们测试了重组人细胞因子，包括白细胞介素（IL）-1、IL-2、IL-4、IL-6、干扰素（IFN）-γ和肿瘤坏死因子（TNF），对γ/δ + T细胞介导的细胞毒性的影响。结果表明，在共孵育中添加重组TNF可增强γ/δ + T细胞对两种膀胱肿瘤细胞系的杀伤作用，但对红白血病细胞系K562的细胞无此作用。基于这些结果得出结论，分枝杆菌抗原可特异性激活静息的γ/δ + T细胞。γ/δ + T细胞对膀胱肿瘤细胞的细胞毒性及其被TNF的选择性增强可能是膀胱内滴注BCG诱导膀胱肿瘤消退的重要机制。
