Department of Microbiology and Immunology, SUNY Upstate Medical University, 766 Irving Ave, Weiskotten Hall Suite 2281, Syracuse, NY 13210, USA.
Department of Pathology, SUNY Upstate Medical University, 766 Irving Ave, Weiskotten Hall Suite 2141, Syracuse, NY 13210, USA.
J Leukoc Biol. 2023 May 2;113(5):489-503. doi: 10.1093/jleuko/qiad019.
Regulatory T cells are suppressive immune cells used in various clinical and therapeutic applications. Canonical regulatory T cells express CD4, FOXP3, and CD25, which are considered definitive markers of their regulatory T-cell status when expressed together. However, a subset of noncanonical regulatory T cells expressing only CD4 and FOXP3 have recently been described in some infection contexts. Using a unique mouse model for the first time demonstrated that the TCF-1 regulation of regulatory T-cell suppressive function is not limited to the thymus during development. Our data showed that TCF-1 also regulated regulatory T cells' suppressive ability in secondary organs and graft-vs-host disease target organs as well as upregulating noncanonical regulatory T cells. Our data demonstrated that TCF-1 regulates the suppressive function of regulatory T cells through critical molecules like GITR and PD-1, specifically by means of noncanonical regulatory T cells. Our in vitro approaches show that TCF-1 regulates the regulatory T-cell effector-phenotype and the molecules critical for regulatory T-cell migration to the site of inflammation. Using in vivo models, we show that both canonical and noncanonical regulatory T cells from TCF-1 cKO mice have a superior suppressive function, as shown by their ability to control conventional T-cell proliferation, avert acute graft-vs-host disease, and limit tissue damage. Thus, for the first time, we provide evidence that TCF-1 negatively regulates the suppressive ability of canonical and noncanonical regulatory T cells. These findings provide evidence that TCF-1 is a novel target for developing strategies to treat alloimmune disorders.
调节性 T 细胞是一种具有抑制作用的免疫细胞，在各种临床和治疗应用中都有使用。经典的调节性 T 细胞表达 CD4、FOXP3 和 CD25，当它们共同表达时，被认为是其调节性 T 细胞状态的明确标志物。然而，最近在一些感染情况下描述了一种只表达 CD4 和 FOXP3 的非经典调节性 T 细胞亚群。首次使用独特的小鼠模型证明，TCF-1 对调节性 T 细胞抑制功能的调控不仅局限于发育过程中的胸腺。我们的数据表明，TCF-1 还调节了次级器官和移植物抗宿主病靶器官中调节性 T 细胞的抑制能力，并上调了非经典调节性 T 细胞。我们的数据表明，TCF-1 通过 GITR 和 PD-1 等关键分子调节调节性 T 细胞的抑制功能，特别是通过非经典调节性 T 细胞。我们的体外方法表明，TCF-1 通过调节调节性 T 细胞效应表型和调节性 T 细胞向炎症部位迁移的关键分子来调节调节性 T 细胞的效应表型。使用体内模型，我们表明 TCF-1 cKO 小鼠的经典和非经典调节性 T 细胞都具有优越的抑制功能，这表现在它们能够控制常规 T 细胞的增殖、避免急性移植物抗宿主病和限制组织损伤。因此，我们首次提供了证据表明 TCF-1 负调节经典和非经典调节性 T 细胞的抑制能力。这些发现为开发治疗同种免疫疾病的策略提供了证据，表明 TCF-1 是一个新的靶点。
