CD4⁺ T cell activation and differentiation are important events that set the stage for proper immune responses. Many factors are involved in the activation and differentiation of T cells, and these events are tightly controlled to prevent unwanted and/or exacerbated immune responses that may harm the host. It has been well-documented that granzyme B, a potent serine protease involved in cell-mediated cytotoxicity, is readily expressed by certain CD4⁺ T cells, such as regulatory T cells and CD4⁺CD8αα⁺ intestinal intraepithelial lymphocytes, both of which display cytotoxicity associated with granzyme B. However, because not all CD4⁺ T cells expressing granzyme B are cytotoxic, additional roles for this protease in CD4⁺ T cell biology remain unknown. Here, using a combination of in vivo and in vitro approaches, we report that granzyme B-deficient CD4⁺ T cells display increased IL-17 production. In the adoptive transfer model of intestinal inflammation, granzyme B-deficient CD4⁺ T cells triggered a more rapid disease onset than their WT counterparts, and presented a differential transcription profile. Similar results were also observed in granzyme B-deficient mice infected with Citrobacter rodentium. Our results suggest that granzyme B modulates CD4⁺ T cell differentiation, providing a new perspective into the biology of this enzyme.

CD4 ⁺ T 细胞激活和分化是为适当的免疫反应奠定基础的重要事件。许多因素都参与了 T 细胞的激活和分化，并且这些事件受到严格控制，以防止可能伤害宿主的不需要的和/或加剧的免疫反应。有充分证据表明，颗粒酶 B 是一种参与细胞介导的细胞毒性的有效丝氨酸蛋白酶，很容易由某些 CD4 ⁺ T 细胞表达，例如调节性 T 细胞和 CD4 ⁺ CD8αα ⁺肠上皮内淋巴细胞，两者均显示出细胞毒性与颗粒酶 B 相关。但是，因为并非所有 CD4 ⁺表达颗粒酶 B 的 T 细胞具有细胞毒性，这种蛋白酶在 CD4 ⁺ T 细胞生物学中的其他作用仍然未知。在这里，我们结合使用体内和体外方法，报告了颗粒酶 B 缺陷型 CD4 ⁺ T 细胞显示出 IL-17 产量增加。在肠道炎症的过继转移模型中，颗粒酶 B 缺陷型 CD4 ⁺ T 细胞比其 WT 对应物引发更快的疾病发作，并呈现差异转录谱。在感染了柠檬酸杆菌的颗粒酶 B 缺陷小鼠中也观察到了类似的结果。我们的结果表明，颗粒酶 B 调节 CD4 ⁺ T 细胞分化，为这种酶的生物学提供了新的视角。