Hoek Kristen L, Greer Michael J, McClanahan Kathleen G, Nazmi Ali, Piazuelo M Blanca, Singh Kshipra, Wilson Keith T, Olivares-Villagómez Danyvid
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Biomedical Informatics, Vanderbilt University, Nashville, TN, USA.
Mucosal Immunol. 2021 Sep;14(5):1088-1099. doi: 10.1038/s41385-021-00427-1. Epub 2021 Jun 28.
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 CD4CD8αα 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细胞的激活和分化是启动适当免疫反应的重要事件。T细胞的激活和分化涉及许多因素，并且这些事件受到严格控制，以防止可能损害宿主的不必要和/或加剧的免疫反应。已有充分的文献记载，颗粒酶B是一种参与细胞介导的细胞毒性的强效丝氨酸蛋白酶，某些CD4 T细胞，如调节性T细胞和CD4CD8αα肠上皮内淋巴细胞，很容易表达颗粒酶B，这两种细胞均表现出与颗粒酶B相关的细胞毒性。然而，由于并非所有表达颗粒酶B的CD4 T细胞都具有细胞毒性，因此这种蛋白酶在CD4 T细胞生物学中的其他作用仍然未知。在这里，我们结合体内和体外方法，报告颗粒酶B缺陷的CD4 T细胞表现出IL-17产生增加。在肠道炎症的过继转移模型中，颗粒酶B缺陷的CD4 T细胞比野生型对应细胞引发了更快的疾病发作，并呈现出不同的转录谱。在用鼠柠檬酸杆菌感染的颗粒酶B缺陷小鼠中也观察到了类似结果。我们的结果表明，颗粒酶B调节CD4 T细胞分化，为该酶的生物学特性提供了新的视角。
