Bagot M, Nikolova M, Schirm-Chabanette F, Wechsler J, Boumsell L, Bensussan A
Department of Dermatology and Inserm U448, Paris XII University, Créteil, France.
Ann N Y Acad Sci. 2001 Sep;941:31-8. doi: 10.1111/j.1749-6632.2001.tb03708.x.
We have established several tumor T cell lines, both from the skin and from the blood of a patient with an MHC class II-/class I+, CD4+ cutaneous T cell lymphoma (CTCL). These cell lines, like the initial tumor cells, had a CD3+CD4+CD8- phenotype. We also isolated two cytotoxic T lymphocyte clones from the tumor site of this CTCL patient. These clones displayed a CD4+CD8dim+ (TC5) and CD4+CD8- (TC7) phenotype and mediated a specific MHC class I-restricted cytotoxic activity toward noncultured tumor cells and autologous tumor cell lines. Despite surface expression of Fas on tumor cells and Fas-L induction on TC5 and TC7 cell membrane after coculture with autologous tumor cells, the CD4+ CTL clones did not use this cytotoxic mechanism to lyse their specific target. TC7 used a granzyme/perforin-dependent pathway, whereas TC5 used a TRAIL-dependent mechanism. Quantitative analysis of cytokine mRNA expression indicated that while the tumor cells displayed a Th2-type profile, the CTL clones expressed Th1-type cytokines. Preincubation of TIL clones with autologous tumor cells in a short-term culture induced their activation and subsequent amplification of the Th1-type response, which indicates a direct contribution of the malignant cells in the Th1/Th2 imbalance. However, we found that tumor cells produced high amounts of TGF-beta, which could explain the inhibition of a specific antitumor immune response. Another mechanism to avoid the host immune response was the expression of CD158a, CD158b, p70, and CD94/NKG2A inhibitory receptors by tumor-specific lymphocytes. Finally, we present recent data on new antigen structures expressed both by long-term CTCL lines and uncultured tumor cells.
我们从一名患有 MHC II 类阴性/I 类阳性、CD4+皮肤 T 细胞淋巴瘤（CTCL）患者的皮肤和血液中建立了多个肿瘤 T 细胞系。这些细胞系与初始肿瘤细胞一样，具有 CD3+CD4+CD8-表型。我们还从该 CTCL 患者的肿瘤部位分离出两个细胞毒性 T 淋巴细胞克隆。这些克隆表现出 CD4+CD8dim+（TC5）和 CD4+CD8-（TC7）表型，并介导针对未培养肿瘤细胞和自体肿瘤细胞系的特异性 MHC I 类限制性细胞毒性活性。尽管肿瘤细胞表面表达 Fas，且与自体肿瘤细胞共培养后 TC5 和 TC7 细胞膜上诱导表达 Fas-L，但 CD4+CTL 克隆并未利用这种细胞毒性机制裂解其特异性靶标。TC7 使用颗粒酶/穿孔素依赖性途径，而 TC5 使用 TRAIL 依赖性机制。细胞因子 mRNA 表达的定量分析表明，虽然肿瘤细胞表现出 Th2 型特征，但 CTL 克隆表达 Th1 型细胞因子。在短期培养中，将肿瘤浸润淋巴细胞（TIL）克隆与自体肿瘤细胞预孵育可诱导其活化，并随后增强 Th1 型反应，这表明恶性细胞在 Th1/Th2 失衡中起直接作用。然而，我们发现肿瘤细胞产生大量转化生长因子-β（TGF-β），这可能解释了特异性抗肿瘤免疫反应受到抑制的原因。另一种逃避宿主免疫反应的机制是肿瘤特异性淋巴细胞表达 CD158a、CD158b、p70 和 CD94/NKG2A 抑制性受体。最后，我们展示了关于长期 CTCL 细胞系和未培养肿瘤细胞所表达的新抗原结构的最新数据。
