CD4+ T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-γ
CD4+ T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-γ
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DOI：
10.1073/pnas.96.15.8633
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发表时间：
1999-07-20
影响因子：
11.1
通讯作者：
Schreiber, H
中科院分区：
文献类型：
--
作者：
Mumberg, D;Monach, PA;Schreiber, H
CD 4（+）T细胞可以在缺乏CD 8（+）T细胞的情况下在体内清除肿瘤细胞。我们有CD 4（+）T细胞特异性的MHC II类限制性，肿瘤特异性肽来源于突变体核糖体蛋白表达的紫外线诱导肿瘤6132 A-PRO。通过使用特异性中和鼠IFN-γ的mAb和过继转移CD 4（+）T细胞到严重联合免疫缺陷小鼠中，我们表明抗IFN-γ治疗在体内消除了CD 4（+）T细胞介导的肿瘤细胞排斥。肿瘤细胞是MHC II类阴性的，并且IFN-γ在体外不诱导MHC II类表达。因此，肿瘤特异性抗原肽必须由宿主细胞而不是肿瘤细胞呈递。转导分泌IFN-γ的肿瘤细胞在严重联合免疫缺陷小鼠中具有显著降低的生长速率，但IFN-γ在体外不抑制肿瘤细胞的生长。此外，稳定表达显性阴性截短形式的鼠IFN-γ受体α链的肿瘤细胞，因此对IFN-γ不敏感，然而被过继转移的CD 4（+）T细胞排斥。因此，宿主细胞，而不是肿瘤细胞，似乎是IFN-γ的目标。总之，这些结果表明，CD 4（+）T细胞可以通过依赖于IFN-γ的间接机制消除IFN-γ不敏感的MHC II类阴性癌细胞。
CD4(+) T cells can eliminate tumor cells in vivo in the absence of CD8(+) T cells. We have CD4(+) T cells specific for a MHC class II-restricted, tumor-specific peptide derived from a mutant ribosomal protein expressed by the UV light-induced tumor 6132A-PRO. By using neutralizing mAb specific for murine IFN-gamma and adoptive transfer of CD4(+) T cells into severe combined immunodeficient mice, we show that anti-IFN-gamma treatment abolishes the CD4(+) T cell-mediated rejection of the tumor cells in vivo. The tumor cells were MHC class II negative, and IFN-gamma did not induce MHC class II expression in vitro. Therefore, the tumor-specific antigenic peptide must be presented by host cells and not the tumor cells. Tumor cells transduced to secrete IFN-gamma had a markedly reduced growth rate in severe combined immunodeficient mice, but IFN-gamma did not inhibit the growth of the tumor cells in vitro. Furthermore, tumor cells stably expressing a dominant-negative truncated form of the murine IFN-gamma receptor a chain, and therefore insensitive to IFN-gamma, nevertheless were rejected by the adoptively transferred CD4(+) T cells. Thus, host cells, and not tumor cells, seem to be the target of IFN-gamma. Together, these results show that CD4(+) T cells can eliminate IFN-gamma-insensitive, MHC class II-negative cancer cells by an indirect mechanism that depends on IFN-gamma.