Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling
Regulatory T cell-resistant CD8+ T cells induced by glucocorticoid-induced tumor necrosis factor receptor signaling
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DOI：
10.1158/0008-5472.can-07-5839
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发表时间：
2008-07-15
期刊：
影响因子：
11.2
通讯作者：
Shiku, Hiroshi
中科院分区：
文献类型：
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作者：
Nishikawa, Hiroyoshi;Kato, Takuma;Shiku, Hiroshi
我们以前发现，鼠伤寒沙门氏菌载体工程分泌可溶性肿瘤抗原诱导CD 4（+）T细胞对CD 4（+）CD 25（+）调节性T细胞（Treg）的耐药性，糖皮质激素诱导的肿瘤坏死因子受体家族相关基因（GITR）信号参与了这种耐药性的发展。在这项研究中，我们探讨了将GITR配体（GITRL）作为增强癌症疫苗免疫原性的一种方式的潜力。用编码突变的细胞外信号调节激酶2（mERK）的质粒与编码小鼠GITRL的质粒一起或不与编码小鼠GITRL的质粒一起通过基因枪免疫BALB/c小鼠。在初次和二次免疫期间与GITRL共同施用增强了mEPW特异性CD 8（+）T细胞的诱导。抗体耗竭和小基因分析表明，GITRL直接激活CTI，独立于CD 4（+）T细胞的表位特异性CD 8（+）T细胞。用编码CTL表位和GITRL的质粒免疫导致以CD 8（+）T细胞依赖性方式的强肿瘤抑制。此外，与没有GITR信号传导诱导的CD 8（+）T细胞相比，通过用编码CTL表位的质粒与GITRL共施用免疫诱导的CTL表位特异性CD 8（+）T细胞对CD 4（+）CD 25（+）T细胞的抑制是难治的。我们提出，GITR信号传导剂与肿瘤抗原的共同给药构成了癌症疫苗开发的一种有前途的新策略。
We previously found that a Salmonella typhimurium vector engineered to secrete soluble tumor antigen induces CD4(+) T cells resistant to CD4(+)CD25(+) regulatory T cells (Treg) and that glucocorticoid-induced tumor necrosis factor receptor familyrelated gene (GITR) signal is involved in the development of this resistance. In this study, we address the potential of incorporating GITR ligand (GITRL) as a way to augment the immunogenicity of cancer vaccines. BALB/c mice were immunized by gene gun with plasmids encoding the mutated extracellular signal-regulated kinase 2 (mERK) with or without plasmids encoding mouse GITRL. Coadministration with GITRL during primary and secondary immunization enhanced the induction of mEPW-specific CD8(+) T cells. Antibody depletion and minigene analysis suggested that GITRL directly activated CTI, epitope-specific CD8(+) T cells independently of CD4(+) T cells. Immunization with plasmids encoding a CTL epitope and GITRL resulted in strong tumor inhibition in a CD8(+) T cell-dependent manner. Furthermore, CTL epitope-specific CD8(+)' T cells induced by immunization with plasmids encoding CTL epitope coadministered with GITRL were refractory to suppression by CD4(+)CD25(+) Tregs compared with CD8(+) T cells induced without GITR signaling. We propose that coadministration of GITR signaling agents with tumor antigens constitutes a promising novel strategy for cancer vaccine development.