In addition to helper and regulatory potential, CD4+ T cells also acquire cytotoxic activity marked by granzyme B (GzmB) expression and the ability to promote rejection of established tumors. Here, we examined the molecular and cellular mechanisms underpinning the differentiation of cytotoxic CD4+ T cells following immunotherapy. CD4+ transfer into lymphodepleted animals or regulatory T (Treg) cell depletion promoted GzmB expression by tumor-infiltrating CD4+, and this was prevented by interleukin-2 (IL-2) neutralization. Transcriptional analysis revealed a polyfunctional helper and cytotoxic phenotype characterized by the expression of the transcription factors T-bet and Blimp-1. While T-bet ablation restricted interferon-γ (IFN-γ) production, loss of Blimp-1 prevented GzmB expression in response to IL-2, suggesting two independent programs required for polyfunctionality of tumor-reactive CD4+ T cells. Our findings underscore the role of Treg cells, IL-2, and Blimp-1 in controlling the differentiation of cytotoxic CD4+ T cells and offer a pathway to enhancement of anti-tumor activity through their manipulation.

中文翻译：

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调节性 T 细胞抑制 CD4+ T 细胞依赖白介素 2 和 Blimp-1 获得细胞毒性功能。

除了辅助和调节潜力外，CD4+ T 细胞还获得了以颗粒酶 B (GzmB) 表达为标志的细胞毒活性和促进已建立肿瘤排斥的能力。在这里，我们检查了免疫治疗后细胞毒性 CD4+ T 细胞分化的分子和细胞机制。CD4+ 转移到淋巴耗竭动物或调节性 T (Treg) 细胞耗竭通过肿瘤浸润 CD4+ 促进 GzmB 表达，而白细胞介素-2 (IL-2) 中和可防止这种情况发生。转录分析揭示了以转录因子 T-bet 和 Blimp-1 的表达为特征的多功能辅助和细胞毒性表型。虽然 T-bet 消融限制了干扰素-γ (IFN-γ) 的产生，但 Blimp-1 的缺失阻止了 GzmB 响应 IL-2 的表达，表明肿瘤反应性 CD4+ T 细胞的多功能性需要两个独立的程序。我们的研究结果强调了 Treg 细胞、IL-2 和 Blimp-1 在控制细胞毒性 CD4+ T 细胞分化中的作用，并通过它们的操作提供了增强抗肿瘤活性的途径。