Enhancing long-term persistence while simultaneously potentiating the effector response of CD8⁺ T cells has been a long-standing goal in immunology to produce better vaccines and adoptive cell therapy products. NR4A3 is a transcription factor of the orphan nuclear receptor family. While it is rapidly and transiently expressed following T cell activation, its role in the early stages of T cell response is unknown. We show that NR4A3-deficient murine CD8⁺ T cells differentiate preferentially into memory precursor and central memory cells, but also produce more cytokines. This is explained by an early influence of NR4A3 deficiency on the memory transcriptional program and on accessibility of chromatin regions with motifs for bZIP transcription factors, which impacts the transcription of Fos/Jun target genes. Our results reveal a unique and early role for NR4A3 in programming CD8⁺ T cell differentiation and function. Manipulating NR4A3 activity may represent a promising strategy to improve vaccination and T cell therapy.

在增强更好的疫苗和过继性细胞治疗产品的免疫学领域，长期目标是增强长期持久性，同时增强CD8 ⁺ T细胞的效应反应。NR4A3是孤儿核受体家族的转录因子。尽管它在T细胞活化后迅速而短暂地表达，但在T细胞应答的早期阶段中的作用尚不清楚。我们证明了NR4A3缺陷型鼠CD8 ⁺T细胞优先分化为记忆前体细胞和中央记忆细胞，但也会产生更多的细胞因子。NR4A3缺乏对记忆转录程序和带有bZIP转录因子基序的染色质区域可及性的早期影响可以解释，这会影响Fos / Jun目标基因的转录。我们的结果揭示了NR4A3在CD8 ⁺ T细胞分化和功能编程中的独特而早期的作用。操纵NR4A3活性可能代表改善疫苗接种和T细胞疗法的有前途的策略。