Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America.
PLoS One. 2012;7(9):e46241. doi: 10.1371/journal.pone.0046241. Epub 2012 Sep 27.
Complex interactions between effector T cells and Foxp3(+) regulatory T cells (Treg) contribute to clinical outcomes in cancer, and autoimmune and infectious diseases. Previous work showed that IL-12 reversed Treg-mediated suppression of CD4(+)Foxp3(-) T cell (Tconv) proliferation. We and others have also shown that Tregs express T-bet and IFN-γ at sites of Th1 inflammation and that IL-12 induces IFN-γ production by Tregs in vitro. To investigate whether loss of immunosuppression occurs when IFN-γ is expressed by Tregs we treated mouse lymphocyte cultures with IL-12. IFN-γ expression did not decrease the ability of Tregs to suppress Tconv proliferation. Rather, IL-12 treatment decreased Treg frequency and Foxp3 levels in Tregs. We further showed that IL-12 increased IL-2R expression on Tconv and CD8 T cells, diminished its expression on Tregs and decreased IL-2 production by Tconv and CD8 T cells. Together, these IL-12 mediated changes favored the outgrowth of non-Tregs. Additionally, we showed that treatment with a second cytokine, IL-27, decreased IL-2 expression without augmenting Tconv and CD8 T cell proliferation. Notably, IL-27 only slightly modified levels of IL-2R on non-Treg T cells. Together, these results show that IL-12 has multiple effects that modify the balance between Tregs and non-Tregs and support an important role for relative levels of IL-2R but not for IFN-γ expression in IL-12-mediated reversal of Treg immunosuppression.
效应 T 细胞和 Foxp3(+)调节性 T 细胞 (Treg) 之间的复杂相互作用导致癌症、自身免疫和传染病的临床结果。先前的工作表明，IL-12 逆转了 Treg 对 CD4(+)Foxp3(-)T 细胞 (Tconv) 增殖的抑制作用。我们和其他人还表明，Tregs 在 Th1 炎症部位表达 T-bet 和 IFN-γ，并且 IL-12 在体外诱导 Tregs 产生 IFN-γ。为了研究当 Tregs 表达 IFN-γ 时是否会失去免疫抑制作用，我们用 IL-12 处理小鼠淋巴细胞培养物。IFN-γ 的表达并没有降低 Tregs 抑制 Tconv 增殖的能力。相反，IL-12 处理降低了 Treg 的频率和 Foxp3 水平。我们进一步表明，IL-12 增加了 Tconv 和 CD8 T 细胞上的 IL-2R 表达，降低了 Tregs 上的表达，并减少了 Tconv 和 CD8 T 细胞的 IL-2 产生。总的来说，这些 IL-12 介导的变化有利于非 Tregs 的生长。此外，我们还表明，用第二种细胞因子 IL-27 处理可降低 IL-2 的表达，而不增强 Tconv 和 CD8 T 细胞的增殖。值得注意的是，IL-27 仅略微改变了非 Treg T 细胞上的 IL-2R 水平。综上所述，这些结果表明，IL-12 具有多种作用，可改变 Treg 和非 Treg 之间的平衡，并支持相对水平的 IL-2R 而不是 IFN-γ 表达在 IL-12 介导的 Treg 免疫抑制逆转中起重要作用。
