Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.

中文翻译：

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Runx3 程序化 CD8+ T 细胞在非淋巴组织和肿瘤中的驻留


组织驻留记忆 CD8+ T (TRM) 细胞存在于病原体暴露的常见部位，在那里它们会引发快速而强大的保护性免疫反应。然而，控制 TRM 细胞分化和稳态的分子信号尚不完全清楚。在这里，我们证明小鼠 TRM 前体细胞代表了独特的 CD8+ T 细胞亚群，其在基因表达和染色质可及性水平上与循环记忆细胞群的前体不同。通过计算和汇总体内 RNA 干扰筛选，我们确定转录因子 Runx3 是 TRM 细胞分化和稳态的关键调节因子。 Runx3需要在不同的组织环境中建立TRM细胞群，并支持关键组织驻留基因的表达，同时抑制与组织流出和再循环相关的基因。此外，我们发现人和小鼠肿瘤浸润淋巴细胞与 TRM 细胞共享核心组织驻留基因表达特征，该特征与 Runx3 活性相关。在黑色素瘤过继性 T 细胞疗法的小鼠模型中，Runx3 缺陷的 CD8+ 肿瘤浸润淋巴细胞未能在肿瘤中积累，导致肿瘤生长率和死亡率更高。相反，Runx3 的过度表达增强了肿瘤特异性 CD8+ T 细胞丰度，延迟了肿瘤生长并延长了生存期。除了将 Runx3 确立为 TRM 细胞分化的中央调节因子之外，这些结果还提供了对促进 T 细胞驻留在非淋巴部位的信号的深入了解，这可用于增强疫苗功效或针对癌症的过继性细胞疗法。