Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
Department of Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Cell Rep. 2020 Nov 3;33(5):108328. doi: 10.1016/j.celrep.2020.108328.
Nr4a receptors are activated by T cell receptor (TCR) signaling and play key roles in T cell differentiation. Which TCR signaling pathways regulate Nr4a receptors and their sensitivities to TCR signal strength and duration remains unclear. Using Nr4a1/Nur77-GFP and Nr4a3-Timer of cell kinetics and activity (Tocky) mice, we elucidate the signaling pathways governing Nr4a receptor expression. We reveal that Nr4a1-Nr4a3 are Src family kinase dependent. Moreover, Nr4a2 and Nr4a3 are attenuated by calcineurin inhibitors and bind nuclear factor of activated T cells 1 (NFAT1), highlighting a necessary and sufficient role for NFAT1 in the control of Nr4a2 and Nr4a3, but redundancy for Nr4a1. Nr4a1-GFP is activated by tonic and cognate signals during T cell development, whereas Nr4a3-Tocky requires cognate peptide:major histocompatibility complex (MHC) interactions for expression. Compared to Nr4a3-Tocky, Nr4a1-GFP is approximately 2- to 3-fold more sensitive to TCR signaling and is detectable by shorter periods of TCR signaling. These findings suggest that TCR signal duration may be an underappreciated aspect influencing the developmental fate of T cells in vivo.
NR4A 受体被 T 细胞受体 (TCR) 信号激活，在 T 细胞分化中发挥关键作用。哪些 TCR 信号通路调节 NR4A 受体及其对 TCR 信号强度和持续时间的敏感性尚不清楚。使用 Nr4a1/Nur77-GFP 和 Nr4a3-Timer of cell kinetics and activity (Tocky) 小鼠，我们阐明了调节 NR4A 受体表达的信号通路。我们揭示了 Nr4a1-Nr4a3 依赖于Src 家族激酶。此外，钙调神经磷酸酶抑制剂减弱了 Nr4a2 和 Nr4a3 的表达，并与活化 T 细胞核因子 1 (NFAT1) 结合，突出了 NFAT1 在控制 Nr4a2 和 Nr4a3 中的必要和充分作用，但对于 Nr4a1 则存在冗余。Nr4a1-GFP 在 T 细胞发育过程中被持续和同源信号激活，而 Nr4a3-Tocky 则需要同源肽：主要组织相容性复合物 (MHC) 相互作用才能表达。与 Nr4a3-Tocky 相比，Nr4a1-GFP 对 TCR 信号的敏感性大约高 2-3 倍，并且可以通过较短的 TCR 信号检测到。这些发现表明，TCR 信号持续时间可能是影响体内 T 细胞发育命运的一个被低估的方面。
