The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Nat Commun. 2023 Oct 23;14(1):6727. doi: 10.1038/s41467-023-42455-4.
Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8 T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with 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.
针对细胞内病原体的有效反应的特点是 T 细胞克隆对其同源肽具有广泛的亲和力范围和多样化的功能表型。T 细胞克隆在整个反应过程中是如何被选择以保持广泛的亲和力仍不清楚。在这里，我们证明 CD8 T 细胞对细胞因子 IFN-γ的直接感知在感染过程中协调了亲和力和分化。IFN-γ促进低亲和力 T 细胞的扩增，使它们能够克服高亲和力 T 细胞的优势，同时加强高亲和力 T 细胞进入记忆池，从而降低初级反应的平均亲和力，增加记忆反应的亲和力。在这种情况下，IFN-γ主要由虚拟记忆 T 细胞提供，这是一个具有记忆特征但无抗原经验的亚群。总的来说，我们提出 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。
