Development of tissue-resident memory (T_RM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5^hi PD-1^hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R^−/−) fail to become bT_RM. IL-21⁺ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R^−/− brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack T_RM core signature genes. CD4 T cell–deficient and IL21R^−/− brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell–depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5^hi PD-1^hi CD4 T cells in the brain produce IL-21, which drives CD8 bT_RM differentiation in response to a persistent viral infection.

组织驻留记忆 (T _RM ) CD8 T 细胞的发展依赖于 CD4 T 细胞。在多瘤病毒中枢神经系统感染中，脑CXCR5 ^hi PD-1 ^hi CD4 T细胞产生白细胞介素21（IL-21），而缺乏IL-21受体（IL21R ^-/-）的CD8 T细胞不能成为bT _RM。IL-21 ⁺ CD4 T 细胞表现出升高的 T 细胞受体 (TCR) 亲和力和更高的 TCR 密度。IL21R ^-/-脑 CD8 T 细胞不表达 CD103，依赖血管 CD8 T 细胞进行维持，抗原召回缺陷，缺乏 T _RM核心特征基因。CD4 T 细胞缺陷和 IL21R ^-/-脑 CD8 T 细胞在氧化代谢基因表达方面表现出类似的缺陷，并且向 CD4 T 细胞耗尽的小鼠鞘内递送 IL-21 可将 CD8 T 细胞中电子传递基因的表达恢复到野生型水平。因此，大脑中的高亲和力 CXCR5 ^hi PD-1 ^hi CD4 T 细胞产生 IL-21，它驱动 CD8 bT _RM分化以响应持续的病毒感染。