Basic Science Program, Science Applications International Corporation-Frederick, Inc., National Cancer Institute, Frederick, MD 21702, USA.
J Immunol. 2010 Jul 1;185(1):174-82. doi: 10.4049/jimmunol.0903548. Epub 2010 Jun 4.
Our previous study showed that TNFR2 is preferentially expressed by CD4(+)FoxP3(+) regulatory T cells (Tregs), and expression of this receptor identified maximally suppressive Tregs. TNFR2 is also expressed by a small fraction of CD4(+)FoxP3(-) conventional T cells (Tconvs) in normal mice, and its expression is upregulated by T cell activation. This raises questions about the role of TNFR2 signaling in the function of Tconv cells. In this study, by using FoxP3/gfp knock-in mice, we showed that TNFR2 signaling did not induce FoxP3(-) CD4 cells to become suppressive. Ki-67, a marker of proliferation, was concomitantly expressed with TNFR2 by CD4 cells, independent of forkhead box P3 expression, in normal mice and Lewis lung carcinoma-bearing mice. TNFR2 is associated with greater suppressive functions when expressed by Tregs and is associated with greater resistance to suppression when expressed by Tconv cells. In mice bearing 4T1 breast tumor or Lewis lung carcinoma, intratumoral Tconv cells expressing elevated levels of TNFR2 acquired the capacity to resist suppression by lymph node-derived Tregs. However, they remained susceptible to inhibition by more suppressive tumor-infiltrating Tregs, which expressed higher levels of TNFR2. Our data indicate that TNFR2 also costimulates Tconv cells. However, intratumoral Tregs expressing more TNFR2 are able to overcome the greater resistance to suppression of intratumoral Tconv cells, resulting in a dominant immunosuppressive tumor environment.
我们之前的研究表明，TNFR2 优先表达于 CD4+FoxP3+调节性 T 细胞（Tregs），且该受体的表达可鉴定出具有最大抑制功能的 Tregs。在正常小鼠中，TNFR2 也表达于一小部分 CD4+FoxP3-常规 T 细胞（Tconvs），其表达可被 T 细胞激活所上调。这引发了关于 TNFR2 信号在 Tconv 细胞功能中的作用的问题。在这项研究中，我们通过使用 FoxP3/gfp 基因敲入小鼠，表明 TNFR2 信号不会诱导 FoxP3- CD4 细胞成为抑制性细胞。Ki-67 是增殖的标志物，在正常小鼠和 Lewis 肺癌荷瘤小鼠中，与 TNFR2 一起由 CD4 细胞表达，与 FoxP3 表达无关。TNFR2 在 Tregs 中表达时与更强的抑制功能相关，在 Tconv 细胞中表达时与更强的抗抑制能力相关。在携带 4T1 乳腺癌或 Lewis 肺癌的小鼠中，表达高水平 TNFR2 的肿瘤内 Tconv 细胞获得了抵抗淋巴结来源的 Tregs 抑制的能力。然而，它们仍然容易受到表达更高水平 TNFR2 的更多具有抑制功能的肿瘤浸润性 Tregs 的抑制。我们的数据表明，TNFR2 也共刺激 Tconv 细胞。然而，表达更多 TNFR2 的肿瘤内 Tregs 能够克服肿瘤内 Tconv 细胞对抑制的更大抗性，导致占主导地位的免疫抑制肿瘤微环境。
