Early programming of CD8⁺ T cell response by the orphan nuclear receptor NR4A3

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.