Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA; Department of Biology, MIT, Cambridge, MA 02139, USA.
Koch Institute for Integrative Cancer Research, MIT, Cambridge, MA 02139, USA.
Immunity. 2023 Feb 14;56(2):386-405.e10. doi: 10.1016/j.immuni.2023.01.010. Epub 2023 Feb 2.
Local environmental factors influence CD8 T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8 T cell responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.
局部环境因素会影响淋巴结（LNs）中的 CD8 T 细胞的初始激活。在这里，我们试图了解纵隔引流淋巴结（mLN）中特有的因素如何影响针对肺癌的 CD8 T 细胞反应。1 型传统树突状细胞（DC1）在诱导强大的细胞毒性 T 细胞反应方面表现出 mLN 特有的失败。使用调节性 T（Treg）细胞耗竭策略，我们发现 Treg 细胞以空间协调的方式在 mLN 内的组织特异性微龛中抑制 DC1。Treg 细胞的抑制需要 MHC II 依赖性的 DC1 和 Treg 细胞之间的接触。IFN-γ 的升高促使 Treg 细胞在 mLN 中分化为 Th1 样效应 Treg 细胞。在癌症患者中，Treg 细胞的 Th1 极化，而不是 CD8/Treg 细胞比例，与对检查点阻断免疫治疗的反应不良相关。因此，mLN 中的 IFN-γ 使 Treg 细胞偏向 Th1 样效应 Treg 细胞，促使它们与 DC1 密切相互作用，从而抑制细胞毒性 T 细胞反应。
