Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France.
Université de Paris, Institut Cochin, CNRS, INSERM, Paris, France
J Immunol. 2021 Jul 1;207(1):15-22. doi: 10.4049/jimmunol.2000392. Epub 2021 Jun 28.
IFN-γ secretion by Ag-specific T cells is known to be tightly regulated by engagement of the TCR. Human plasmacytoid dendritic cells (pDC) can cross-present Ags from apoptotic HIV-infected cells or tumor cells to CD8 T cells. As pDC respond to HIV virions by maturing and secreting cytokines, we hypothesized that this might affect cross-presentation from HIV-infected cells. Purified blood DC were incubated with apoptotic HIV-infected H9 cells in the presence of saquinavir, after which the activation process of HIV-specific cloned CD8 T cells was studied. IFN-γ secretion by HIV-specific T cells was stimulated by pDC and conventional DC (cDC1) more than by cDC2 and was strictly MHC class I restricted. Surprisingly, intracellular production of IFN-γ was only partly MHC class I restricted for pDC, indicating a noncognate CD8 T cell activation. pDC, but not cDC, matured and secreted IFN-α in the presence of apoptotic H9HIV cells. A mixture of IFN-α, IFN-β, and TNF-α induced intracellular production of IFN-γ but not granzyme B, mimicking the noncognate mechanism. Neutralization of type I IFN signaling blocked noncognate intracellular production of IFN-γ. Moreover, cognate stimulation was required to induce IFN-γ secretion in addition to the cytokine mixture. Thus, IFN-γ secretion is tightly regulated by engagement of the TCR as expected, but in the context of virus-infected cells, pDC can trigger intracellular IFN-γ accumulation in CD8 T cells, potentializing IFN-γ secretion once CD8 T cells make cognate interactions. These findings may help manipulate type I IFN signaling to enhance specifically Ag-specific CD8 T cell activation against chronic infections or tumors.
IFN-γ 的分泌由抗原特异性 T 细胞的 TCR 结合来严格调控。人类浆细胞样树突状细胞（pDC）可以交叉呈递凋亡的 HIV 感染细胞或肿瘤细胞中的抗原给 CD8 T 细胞。由于 pDC 通过成熟和分泌细胞因子来响应 HIV 病毒颗粒，我们假设这可能会影响来自 HIV 感染细胞的交叉呈递。纯化的血液树突状细胞在 saquinavir 的存在下与凋亡的 HIV 感染的 H9 细胞孵育，然后研究 HIV 特异性克隆 CD8 T 细胞的激活过程。pDC 和常规树突状细胞（cDC1）比 cDC2 更能刺激 HIV 特异性 T 细胞分泌 IFN-γ，并且严格受到 MHC I 类限制。令人惊讶的是，pDC 对 IFN-γ的细胞内产生仅部分受到 MHC I 类限制，表明存在非同源 CD8 T 细胞激活。pDC 但不是 cDC 在存在凋亡的 H9HIV 细胞时成熟并分泌 IFN-α。IFN-α、IFN-β 和 TNF-α 的混合物诱导 IFN-γ的细胞内产生，但不诱导颗粒酶 B 的产生，模拟非同源机制。I 型 IFN 信号的中和阻断了非同源细胞内 IFN-γ的产生。此外，除了细胞因子混合物外，还需要同源刺激来诱导 IFN-γ 的分泌。因此，正如预期的那样，TCR 的结合严格调控 IFN-γ 的分泌，但在病毒感染细胞的情况下，pDC 可以触发 CD8 T 细胞中 IFN-γ的细胞内积累，一旦 CD8 T 细胞发生同源相互作用，就会增强 IFN-γ 的分泌。这些发现可能有助于操纵 I 型 IFN 信号以增强针对慢性感染或肿瘤的特异性 Ag 特异性 CD8 T 细胞激活。
