Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA.
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02129, USA; Center for Gastrointestinal Biology, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais 31270-901, Brazil.
Immunity. 2022 Jan 11;55(1):82-97.e8. doi: 10.1016/j.immuni.2021.11.002. Epub 2021 Nov 29.
CD8 T cells responding to chronic infection adapt an altered differentiation program that provides some restraint on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8 T cell differentiation in chronic infection has important therapeutic implications. Here, we find that the chemokine receptor CXCR3 is highly expressed on viral-specific stem-like CD8 T cells and that one of its ligands, CXCL10, regulates the persistence and heterogeneity of responding CD8 T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 is produced by inflammatory monocytes and fibroblasts of the splenic red pulp, where it grants stem-like cells access to signals promoting differentiation and limits their exposure to pro-survival niches in the white pulp. Consequently, functional CD8 T cell responses are greater in Cxcl10 mice and are associated with a lower viral set point.
CD8 T 细胞对慢性感染的反应会适应改变的分化程序，这种程序对病原体复制有一定的限制作用，但也限制了免疫病理学。这种适应性会在干细胞样细胞中留下印记，并传播到它们的后代。了解慢性感染中 CD8 T 细胞分化的分子控制具有重要的治疗意义。在这里，我们发现趋化因子受体 CXCR3 在病毒特异性干细胞样 CD8 T 细胞上高度表达，其配体之一 CXCL10 调节慢性淋巴细胞性脉络丛脑膜炎病毒感染小鼠脾脏中应答 CD8 T 细胞的持久性和异质性。CXCL10 由脾脏红髓中的炎症性单核细胞和成纤维细胞产生，它使干细胞样细胞能够获得促进分化的信号，并限制它们暴露于白髓中的生存龛位。因此，Cxcl10 小鼠的功能性 CD8 T 细胞反应更强，与较低的病毒基准点相关。
