Jaiswal, P.K. Li, H.; Kolluri, S.K. 2, C and D). This is further emphasized by emerging evidence suggesting that the induction of individual NR4A family members is differentially regulated downstream of TCR signaling (15). J.A.H., W.S.E. We show that NR4A3-deficient murine CD8 + T cells differentiate preferentially into memory precursor and central memory cells, but also produce more cytokines. ; Goode, J.M. Qing, H.; Liu, Y.; Zhao, Y.; Aono, J.; Jones, K.L. doi: 10.1016/S1074-7613(03)00292-9, 114. Notch Signaling Activation in Cervical Cancer Cells Induces Cell Growth Arrest with the Involvement of the Nuclear Receptor NR4A2. Finally, this section will focus on the role of the NR4A family in αβ-thymocyte selection, since to our knowledge the NR4As have not been reported to regulate the development of any other thymic lineages. doi: 10.1093/nar/gkh856, 118. ; Wen, Q.; Wang, W.J. ; Yan, G.-J. Ohkura, N.; Nagamura, Y.; Tsukada, T. Differential transactivation by orphan nuclear receptor NOR1 and its fusion gene product EWS/NOR1: Possible involvement of poly(ADP-ribose) polymerase I, PARP-1. Nat Immunol (2016) 17:304–14. doi: 10.15252/embj.201490786, 98. Muscle specific Nr4a3 overexpression mice fed a control diet presented with decreased epididymal, inguinal, brown and total adipose mass [, Nr4a’s also play an important role in adipose tissue glucose utilization. EMBO J (2003) 22:6526–36. At the memory stage, the Nr4a transcription was shown to be enriched in a particular subset of memory CD8+ T cells, the resident memory CD8+ T cells (Trm). ; Daugherty, A.; Liang, Y.; et al. The Orphan Nuclear Receptor 4A1: A Potential New Therapeutic Target for Metabolic Diseases. doi: 10.1016/j.immuni.2016.07.021, 103. Lee, S.O. showed that combined deficiency in NR4A1 and Bim, a key inducer of thymocyte apoptosis (54), did not further impair clonal deletion compared to NR4A1-deficiency alone. doi: 10.1074/jbc.M408554200, 83. Therefore, NR4A1 and NR4A3 have a similar impact on cytokine production but not on MPEC/SLEC differentiation, suggesting that these have redundant and non-redundant functions. ; Ramirez-Herrick, A.M.; Duren, R.P. Hotchkiss, R.S. The Nr4a family of nuclear hormone receptors is composed of three members—Nr4a1/Nur77, Nr4a2/Nurr1 and Nr4a3/Nor1. J Exp Med (2005) 201:793–804. ; Sun, Y.; Safe, S. Bis-Indole-Derived NR4A1 Ligands and Metformin Exhibit NR4A1-Dependent Glucose Metabolism and Uptake in C2C12 Cells. Koenis DS, Medzikovic L, Vos M, Beldman TJ, van Loenen PB, van Tiel CM, et al. LO and JM contributed equally to the work. ; Bulun, S.; Chakravarti, D. Expression Profiling of Nuclear Receptors Identifies Key Roles of NR4A Subfamily in Uterine Fibroids. Forced expression of NR4A3 induced the differentiation of human neuroblastoma-derived NB1 cells. Wake, K. Perisinusoidal stellate cells (fat-storing cells, interstitial cells, lipocytes), their related structure in and around the liver sinusoids and vitamin A-storing cells in extrahepatic organs. It is therefore possible that NR4A3 prevents the activity of bZIP transcription factors during CD8+ T cell response. Alonso, J.; Galan, M.; Marti-Pamies, I.; Romero, J.M. Liu, Y.; Zhang, J.; Yi, B.; Chen, M.; Qi, J.; Yin, Y.; Lu, X.; Jasmin, J.-F.; Sun, J. Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation Through Inhibition of the STAT3/Pim-1/NFAT Pathway. For some tumors the Nr4a’s promote proliferation and in others they inhibit it, making modulation of these transcription factors a possible therapeutic target. Nat Rev Immunol (2005) 5:772–82. ; Riviere, I.; Wang, X.; Bartido, S.; Park, J.; Curran, K.; Chung, S.S.; Stefanski, J.; Borquez-Ojeda, O.; Olszewska, M.; et al. ; et al. When Nr4a1 was overexpressed, it inhibited proliferation by blocking the STAT3/Pim-1/NFAT pathway members which decreased Cyclin D1 and PCNA expression [, Nr4a2 has a similar affect in neonatal tunica intima VSMCs as Nr4a1 does in other VSMCs. Pearen MA, Muscat GEO. ; Kim, Y.J. The self-obsession of T cells: how TCR signaling thresholds affect fate “decisions” and effector function. S4E), which does not induce the generation of DC-SIGN + … Proc Natl Acad Sci USA (2001) 98:3690–4. TCR signals received by nascent thymocytes lead to transcriptional changes that regulate positive and negative selection (10). Cnop, M.; Welsh, N.; Jonas, J.C.; Jorns, A.; Lenzen, S.; Eizirik, D.L. NR4A3-C (C-terminal 308 amino acids of NR4A3) fused with a flag tag in the N-terminal and SMARCB1 fused with an HA tag in the N-terminal were coexpressed in HEK-293T cells, followed by an antiflag IP assay. The Nr4a family control regulation of hematopoietic stem cell development [, The extrinsic pathway begins with attachment of ligands to the extracellular domain of transmembrane proteins [, The inhibitor of apoptosis (IAP) family of proteins are critical in the regulation of apoptosis [, The Nr4a family also induces apoptosis in certain cell types. Masuyama N, Oishi K, Mori Y, Ueno T, Takahama Y, Gotoh Y. Akt inhibits the orphan nuclear receptor Nur77 and T-cell apoptosis. ; Stepto, N.K. Intriguingly, most of the DARs are more opened in absence of NR4A3 and within these regions there is an enrichment for the DNA binding motifs for the transcription factors of the bZIP family, which includes Fos and Jun (89). The transcripts that are differentially expressed between Nr4a3+/+ and Nr4a3−/− CD8+ T cells were associated with the signature of memory T cells. Chao, L.C. ; Smyth, A.M.; Petrella, B.L. Nkx6.1 regulates islet beta-cell proliferation via Nr4a1 and Nr4a3 nuclear receptors. ; Kim, J.J.; Ghosh, A.K. Mix, K.S. We use cookies on our website to ensure you get the best experience. Additionally, Fassett et al. ATAC-seq further showed that a large fraction (36%) of DARs with lower accessibility in NR4A triple-deficient TILs contains the NBRE motif. ; de Lima, T.I. Nature (2017) 552:253–7. For efficient activation and differentiation into effector T cells able to control the infection, naïve T cells require three signals: TCR stimulation, co-stimulatory signals provided by mature DCs via CD28-CD80/CD86 interactions, and an inflammatory milieu (cytokines produced by DCs or the environment). doi: 10.1016/j.immuni.2018.01.015, 94. Kasler HG, Lim HW, Mottet D, Collins AM, Lee IS, Verdin E. Nuclear export of histone deacetylase 7 during thymic selection is required for immune self-tolerance. ; Badimon, L.; Rodriguez, C.; Arnal, C.; Noone, E.J. ; de Vos, J.; Bakker, E.; Koenis, D.S. doi: 10.1158/0008-5472.CAN-17-3102, Keywords: NR4A nuclear receptor, CD4 T cell, CD8 T cell, thymus, immune response, Nur77, Nurr1, Nor1, Citation: Odagiu L, May J, Boulet S, Baldwin TA and Labrecque N (2021) Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology. Instead, NR4A2 was necessary for the production of IL-21, which then upregulates the expression of the IL-23 receptor, necessary to enhance and stabilize the Th17 phenotype. beta-Cell deletion of Nr4a1 and Nr4a3 nuclear receptors impedes mitochondrial respiration and insulin secretion. found that NR4A family transcription factors act as transcriptional effectors of T cell dysfunction programs, promoting both the accessibility of dysfunction-related genes and the repression of effector-related genes. The dependence of Treg cells on NR4A expression makes it a possible target for therapy. ; Jiang, W.; D’Alise, A.M.; Mathis, D.; Benoist, C. Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion. Doi Y, Oki S, Ozawa T, Hohjoh H, Miyake S, Yamamura T. Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines. Hu QN, Baldwin TA. doi: 10.1073/pnas.2007224117, 90. It identifies the optimal mouse transgenic status and fluorochromes compatible with the dual reporter. Accelerated Partial Hepatectomy–Induced Liver Cell Proliferation Is Associated with Liver Injury in Nur77 Knockout Mice. Nur77 Regulates Nondeletional Mechanisms of Tolerance in T Cells. The statements, opinions and data contained in the journals are solely The generation of a repertoire of T cells endowed with the ability to recognize almost all the possible foreign Ags is possible due to TCR gene rearrangement, a process where random juxtaposition of TCR gene segments occurs to create TCR sequence diversity. Deutsch, A.J. Cheng LE, Chan FK, Cado D, Winoto A. Functional redundancy of the Nur77 and Nor-1 orphan steroid receptors in T-cell apoptosis. Sun, Z.; Cao, X.; Jiang, M.M. Acinic cell carcinoma (AciCC) harbors a recurrent t(4;9)(q13;q31) translocation, which leads to upregulation of Nuclear Receptor Subfamily 4 Group A Member 3 (NR4A3). J Immunol (2017) 198:657–68. Following Ag recognition of peptide fragments on MHC class II molecules on DCs, naïve CD4+ T cells will proliferate and differentiate into effector cells. Due to this, Nr4a1, Nr4a2 and Nr4a3 are potential therapeutic targets in many cancers, however their specific roles vary between tissues and among tumors from the same organ. They recognize, via their T cell receptor (TCR), a peptide fragment of antigen (Ag) in association with class I or II molecules of the major histocompatibility complex (MHC). Finally, signals that induce cell proliferation and apoptosis are in direct opposition to each other. Laybutt, D.R. Arch Pharm Res (2016) 11:1–7. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. ; Dawson, M.I. Induces gene expression by binding as monomers to the NR4A1 response element (NBRE) 5'-AAAAGGTCA-3' site and as homodimers to the Nur response element (NurRE) site in the promoter of their regulated target genes (By similarity). doi: 10.1073/pnas.0803454105, 115. ; Vos, M.; Mocking, A.I. Front. Silke, J.; Meier, P. Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Kalekar LA, Schmiel SE, Nandiwada SL, Lam WY, Barsness LO, Zhang N, et al. The orphan nuclear receptor TR3/Nur77 regulates ER stress and induces apoptosis via interaction with TRAPgamma. doi: 10.4049/jimmunol.177.10.6660, 39. Lin B, Kolluri SK, Lin F, Liu W, Han Y-H, Cao X, et al. Instead of GFP, Tocky reporter protein possesses time-dependent decay fluorescence shifting its emission from blue to red. This research was funded by the American Diabetes Association, grant number 1-17-IBS-101 (J.S.T. Angiogenesis is also linked to the Nr4a subfamily, making it another target to limit tumor growth. Nat Immunol (2005) 6:761–6. The key enzyme for these functions is retinaldehyde dehydrogenase 2 (RALDH2, encoded by Aldh1a2), which is highly expressed in LPDCs. At the memory stage, Nr4a genes are selectively transcribed by CD8+ Trm cells with the three members possibly contributing to Trm cell differentiation while NR4A3 represses CD8+ Tcm cell generation. NR4A1 and NR4A3 restrict HSC proliferation via reciprocal regulation of C/EBPalpha and inflammatory signaling. In vitro, this occurs within 1h of stimulation, peaks after 3–4h and return to basal level at 12h (38, 69, 112). doi: 10.1074/jbc.M109.072744, 67. Kim, J.-i. A ... most probably because Nr4a1 mRNA is induced more than Nr4a2 or Nr4a3 mRNA after stimulation of the TCR in naive CD4 + T cells. ; Van den Bossche, J.; Speijer, D.; Kim, Y.; et al. doi: 10.1016/j.immuni.2016.10.028, 48. Zhang, L.; Wang, Q.; Liu, W.; Liu, F.; Ji, A.; Li, Y. Cell death. ; Biankin, A.V. The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss. doi: 10.1016/j.jneuroim.2006.02.004, 117. NR4A-family members do not only have a role in the development of regulatory CD4+ T cells, as discussed above, but they are also required to maintain a pool of fully functional Tregs. ; Muscat, G.E. Nr4a1 and Nr4a2 promote lung cancer growth. This increase in NR4A2 expression by autoimmune T cells was not observed in the STZ model of autoimmune diabetes, which is mediated by Th1 cells, suggesting that the enhanced expression of NR4A2 is associated with autoimmune diseases where IL-17 plays a pathogenic role (115). T cell receptor signal strength in Treg and iNKT cell development demonstrated by a novel fluorescent reporter mouse. The dispensability of NR4A1 for UbsA-mediated clonal deletion was further reinforced by a study using the physiological HYcd4 transgenic TCR model (18). Importantly, Nr4a3 −/− mice do not have a generalized defect in T cell priming, as they mounted a normal T cell response following infection with an OVA-expressing strain of the gram-positive bacteria Listeria monocytogenes (Lm-OVA) (SI Appendix, Fig. Saucedo-Cardenas, O.; Kardon, R.; Ediger, T.R. This was combined to a germline Nr4a3 deletion to generate Nr4a triple knockout (TKO) in Foxp3 expressing cells. This binding increasing TPβ activity and increase fatty acid oxidation [. Kuang AA, Cado D, Winoto A. Nur77 transcription activity correlates with its apoptotic function in vivo. Hogquist KA, Baldwin TA, Jameson SC. Impact Factor 3.644 | CiteScore 3.4More on impact ›, Nuclear Receptors and Coregulators in Metabolism and Immunity
Maijenburg, M.W. Reduced NR4A gene dosage leads to mixed myelodysplastic/myeloproliferative neoplasms in mice. Chromatin immunoprecipitation (ChIP) revealed that Nr4a3 directly interacts with the Cyclin D1 promoter, demonstrating that it is a direct Nr4a3 target in hepatocytes [. ; Olalla Saad, S.T. Antigen recognition by naïve CD8+ T cells will induce a transcriptional program responsible for activation, proliferation, and differentiation and proliferation. Roche, E.; Buteau, J.; Aniento, I.; Reig, J.A. In addition to regulating the function of endogenous TIL, NR4As also regulated the function of chimeric antigen receptor (CAR) T cells. An additional outcome of high affinity TCR signaling is the generation of anergic phenotype FR4hi CD73hi CD4+ T cells, which are also thought a precursor to Foxp3+ Tregs (76–78), and which demonstrates enhanced thymic development in a NR4A1-deficient context (18).