Werneck Miriam B F, Lugo-Villarino Geanncarlo, Hwang Eun Sook, Cantor Harvey, Glimcher Laurie H
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
J Immunol. 2008 Jun 15;180(12):8004-10. doi: 10.4049/jimmunol.180.12.8004.
Antitumor responses depend on type 1 immunity, which is severely impaired in mice deficient for the T-box expressed in T cells (T-bet) transcription factor. Both T-bet-deficient (T-bet(-/-)) NK and CTL show defective function, which can be overcome by strong stimuli due to the expression of eomesodermin, another member of the T-box family. The effective response from T-bet(-/-) mice to viral infection and tumor initiation corroborates with these findings. However, T-bet(-/-) animals fail to control cancer metastasis and are, therefore, highly susceptible to tumor spread. The mechanism of T-bet-dependent resistance to metastatic disease is not known. In this study, we show that T-bet plays a role in inhibiting cancer metastasis by regulating the longevity and function of NK cells. Our data demonstrate that the absence of a proper innate immune response driven by NK cells in T-bet(-/-) mice precludes the initiation of a potent adaptive response to tumors. Adoptive transfer of wild-type activated NK cells protects T-bet(-/-) animals after melanoma challenge showing that reconstitution of the NK compartment in these mice is sufficient to mediate a significant reduction in tumor burden. Transfer of T-bet(-/-) A-NK cells fails to do so, due to their reduced in vivo survival, inefficient lysis of cancer cells, and poor IFN-gamma production. Taken together, these results show for the first time an irreplaceable role for T-bet in the NK-mediated cross-talk between innate and adaptive immune responses to metastatic disease.
抗肿瘤反应依赖于1型免疫，而在T细胞中表达的T盒（T-bet）转录因子缺陷的小鼠中，1型免疫严重受损。T-bet缺陷（T-bet(-/-)）的自然杀伤细胞（NK）和细胞毒性T淋巴细胞（CTL）均表现出功能缺陷，由于T盒家族的另一个成员——胚外中胚层决定因子的表达，这种缺陷可被强烈刺激所克服。T-bet(-/-)小鼠对病毒感染和肿瘤起始的有效反应证实了这些发现。然而，T-bet(-/-)动物无法控制癌症转移，因此极易发生肿瘤扩散。T-bet依赖性抵抗转移性疾病的机制尚不清楚。在本研究中，我们表明T-bet通过调节NK细胞的寿命和功能在抑制癌症转移中发挥作用。我们的数据表明，T-bet(-/-)小鼠中由NK细胞驱动的适当先天性免疫反应的缺失，排除了对肿瘤产生有效适应性反应的起始。野生型活化NK细胞的过继转移在黑色素瘤攻击后保护了T-bet(-/-)动物，表明这些小鼠中NK细胞区室的重建足以介导肿瘤负荷的显著降低。T-bet(-/-)活化NK细胞的转移未能做到这一点，因为它们在体内的存活率降低、对癌细胞的裂解效率低下以及干扰素-γ产生不足。综上所述，这些结果首次表明T-bet在NK介导的对转移性疾病的先天性和适应性免疫反应之间的相互作用中具有不可替代的作用。
