Integration of Avidity and Differentiation is enabled by CD8 + T-cell sensing of IFN-?
Integration of Avidity and Differentiation is enabled by CD8 + T-cell sensing of IFN-?
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CD8 T 细胞对 IFN-α 的感应可实现亲合力和分化的整合。
DOI：
10.1101/2023.03.06.531375
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Uhl L
中科院分区：
文献类型：
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作者：
Uhl L
对细胞内病原体最有效的反应需要大量与其同源肽具有不同亲和力的 T 细胞克隆，以及从效应细胞到长寿命记忆细胞的多种功能表型。虽然高亲和力和低亲和力 T 细胞本质上分别倾向于成为效应细胞和记忆细胞，但总体而言，这两种功能子集都利用了广泛的亲和力。因此，亲和力和功能的广度如何协调尚不清楚。在这项研究中，我们提供的证据表明，CD8+T 细胞对细胞因子 IFN-γ 的直接感知是感染过程中控制 T 细胞亲和力和分化整合的一个因素。 IFN-γ 可增加低亲和力 T 细胞的扩增，使其克服高亲和力 T 细胞的选择性优势。与此同时，IFN-γ 增强了高亲和力 T 细胞进入记忆池的能力。因此，CD8+T 细胞对 IFN-γ 的直接感应增加了记忆反应的热情。这是以初级 T 细胞反应为代价的，IFN-γ 会降低初级 T 细胞反应的亲合力，导致对感染的免疫力不佳。 CD8+T 细胞对 IFN-γ 的感知是旁分泌的，由称为虚拟记忆 T 细胞的 CD8+T 细胞的独特子集提供，这是一个具有记忆功能的抗原未经历过的子集。总的来说，我们认为 IFN-γ 和虚拟记忆 T 细胞通过协调 T 细胞的亲和力和命运来发挥关键的免疫调节作用。
The most effective responses to intracellular pathogens have a breadth of T-cell clones with different affinities for their cognate peptide, and a diversity of functional phenotypes, from effector to long-lived memory cells. While high- and low-affinity T-cells are inherently skewed towards becoming effector and memory, respectively, overall, both functional subsets exploit a wide range of affinities. How the breadth of affinities and functionalities are coordinated is therefore unclear. In this study, we provide evidence that direct sensing of the cytokine IFN-γ by CD8+T-cells is a factor controlling the integration of T-cell affinity and differentiation during infection. IFN-γ increases the expansion of low-affinity T-cells, allowing them to overcome the selective advantage of high-affinity T-cells. Concomitantly, IFN-γ reinforces high-affinity T-cell entry into the memory pool. As a result, direct IFN-γ sensing by CD8+T-cells increases the avidity of the memory response. This comes at the expense of the primary T-cell response, for which IFN-γ decreases the avidity, leading to sub-optimum immunity to infection. IFN-γ sensing by CD8+T-cells is paracrine, provided by a distinct subset of CD8+T-cells called Virtual Memory T-cells, an antigen inexperienced subset that harbors memory features. Overall, we propose that IFN-γ and Virtual Memory T-cells fulfil a critical immunoregulatory role by enabling the coordination of T-cell avidity and fate.