Nr4a1 and Nr4a3 Reporter Mice Are Differentially Sensitive to T Cell Receptor Signal Strength and Duration

• DOI: 10.1016/j.celrep.2020.108328
• Publication Date: 2020-11-03T20:23:11Z
• Authors: Emma Jennings; Thomas A.E. Elliot; Natasha Thawait; Shivani Kanabar; Juan Carlos Yam-Puc; Masahiro Ono; Kai-Michael Toellner; David C. Wraith; Graham Anderson; David Bending
• Keywords: CD4-Positive T-Lymphocytes; Male; 570; Receptors, Steroid; NFAT; QH301-705.5; MAP Kinase Signaling System; Green Fluorescent Proteins; Receptors, Antigen, T-Cell; 610; Mice, Transgenic; Nerve Tissue Proteins; CD8-Positive T-Lymphocytes; 0601 Biochemistry and Cell Biology; 03 medical and health sciences; Genes, Reporter; Report; Nuclear Receptor Subfamily 4, Group A, Member 1; Animals; Biology (General); 0303 health sciences; Receptors, Thyroid Hormone; NFATC Transcription Factors; T cell activation; T cell receptor signaling; Calcineurin; T cell development; Nr4a3-Tocky; DNA-Binding Proteins; Mice, Inbred C57BL; 1116 Medical Physiology; Female; Peptides; Nr4a1-GFP; Signal Transduction

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.