Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2012;7(10):e47732. doi: 10.1371/journal.pone.0047732. Epub 2012 Oct 15.
TCRαβ(+) CD4(-)CD8(-)NK(-) double negative T cells (DN T cells) can act as regulatory T cells to inhibit allograft rejection and autoimmunity. Their role in graft-versus-host disease and mechanisms of suppression remain elusive. In this study, we demonstrate that DN T cells can inhibit CD4(+) T cell-mediated GVHD in a semi-allogeneic model of bone marrow transplantation. Furthermore, we present evidence of a novel autocrine IFNγ signaling pathway in Fas-deficient C57BL/6.lpr (B6.lpr) DN T cells. B6.lpr DN T cells lacking IFNγ or its receptor were impaired in their ability to suppress syngeneic CD4(+) T cells responding to alloantigen stimulation both in vitro and in vivo. Autocrine IFNγ signaling was required for sustained B6.lpr DN T cell IFNγ secretion in vivo and for upregulation of surface Fas ligand expression during TCR stimulation. Fas ligand (FasL) expression by B6.lpr DN T cells permitted lysis of activated CD4(+) T cells and was required for suppression of GVHD. Collectively, our data indicate that DN T cells can inhibit GVHD and that IFNγ plays a critical autocrine role in controlling the regulatory function of B6.lpr DN T cells.
TCRαβ(+) CD4(-)CD8(-)NK(-) 双阴性 T 细胞 (DN T 细胞) 可作为调节性 T 细胞抑制同种异体移植物排斥和自身免疫。它们在移植物抗宿主病中的作用及其抑制机制仍不清楚。在本研究中，我们证明了 DN T 细胞可以在骨髓移植的半同种异体模型中抑制 CD4(+) T 细胞介导的移植物抗宿主病。此外，我们提出了在 Fas 缺陷的 C57BL/6.lpr (B6.lpr) DN T 细胞中存在新型自分泌 IFNγ 信号通路的证据。缺乏 IFNγ 或其受体的 B6.lpr DN T 细胞在体外和体内抑制同种抗原刺激的同源 CD4(+) T 细胞反应的能力受损。自分泌 IFNγ 信号通路是 B6.lpr DN T 细胞在体内持续分泌 IFNγ和在 TCR 刺激期间上调表面 Fas 配体表达所必需的。B6.lpr DN T 细胞表达 Fas 配体 (FasL) 可裂解活化的 CD4(+) T 细胞，且抑制移植物抗宿主病所必需的。总之，我们的数据表明 DN T 细胞可以抑制移植物抗宿主病，IFNγ 在控制 B6.lpr DN T 细胞的调节功能方面发挥着关键的自分泌作用。
