Although treatment with the glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) agonistic antibody (DTA-1) has shown antitumor activity in various tumor models, the underlying mechanism is not fully understood. Here, we demonstrate that interleukin (IL)-21-producing follicular helper T (Tfh) cells play a crucial role in DTA-1-induced tumor inhibition. The administration of DTA-1 increased IL21 expression by Tfh cells in an antigen-specific manner, and this activation led to enhanced antitumor cytotoxic T lymphocyte (CTL) activity. Mice treated with an antibody that neutralizes the IL21 receptor exhibited decreased antitumor activity when treated with DTA-1. Tumor growth inhibition by DTA-1 was abrogated in Bcl6 fl/fl Cd4 Cre mice, which are genetically deficient in Tfh cells. IL4 was required for optimal induction of IL21-expressing Tfh cells by GITR costimulation, and c-Maf mediated this pathway. Thus, our findings identify GITR costimulation as an inducer of IL21-expressing Tfh cells and provide a mechanism for the antitumor activity of GITR agonism.

中文翻译：

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GITR拮抗作用通过表达IL21的卵泡辅助性T细胞触发抗肿瘤免疫反应。

尽管糖皮质激素诱导的肿瘤坏死因子受体相关蛋白（GITR）激动抗体（DTA-1）的治疗在各种肿瘤模型中均显示出抗肿瘤活性，但其潜在机制尚未完全明了。在这里，我们证明，产生白介素（IL）-21的卵泡辅助性T（Tfh）细胞在DTA-1诱导的肿瘤抑制中起关键作用。DTA-1的施用以抗原特异性方式增加了Tfh细胞的IL21表达，并且这种激活导致增强的抗肿瘤细胞毒性T淋巴细胞（CTL）活性。当用DTA-1处理时，用中和IL21受体的抗体处理的小鼠表现出降低的抗肿瘤活性。在Tfh细胞中遗传缺陷的Bcl6 fl / fl Cd4 Cre小鼠中，取消了DTA-1对肿瘤的生长抑制作用。IL4是通过GITR共刺激最佳诱导表达IL21的Tfh细胞所必需的，而c-Maf介导该途径。因此，我们的发现将GITR共刺激识别为表达IL21的Tfh细胞的诱导剂，并为GITR激动的抗肿瘤活性提供了一种机制。