Nuclear receptor Nr4a1 modulates both regulatory T-cell (Treg) differentiation and clonal deletion

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 109; no. 10; pp. 3891 - 3896
• Main Authors: Fassett, Marlys S, Jiang, Wenyu, D'Alise, Anna Morena, Mathis, Diane, Benoist, Christophe
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06.03.2012; National Acad Sciences
• Subjects: AKT protein; Animals; Apoptosis; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11; BIM protein; Biological Sciences; Cell Differentiation; Cell fate; Cell Lineage; Cell Nucleus - metabolism; Clonal deletion; Cloning; Differentiation; Enzymes; Foxp3 protein; Genes; Glycolysis; Immunoregulation; Liver; Lymphocytes T; Membrane Proteins - metabolism; Mice; Mice, Knockout; Natural killer T cells; Negative selection; Nuclear Receptor Subfamily 4, Group A, Member 1 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 1 - physiology; Nuclear receptors; Nur77 protein; Peptides - chemistry; Proto-Oncogene Proteins - metabolism; receptors; Rodents; Signatures; T cell antigen receptors; T cell receptors; T lymphocytes; T-cell receptor; T-Lymphocytes, Regulatory - cytology; Thymocytes; Thymocytes - cytology; Time Factors; TOR protein; transcription (genetics); Transcription factors; Transcription Factors - metabolism; Transgenic animals; Transgenic mice; Tricarboxylic acid cycle
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1200090109

Immature thymocytes expressing autoreactive T-cell receptors (TCR) can adopt differing cell fates: clonal deletion by apoptosis or deviation into alternative lineages such as FoxP3+ regulatory T cells (Treg). We revisited the role of the transcription factor Nr4a1 (Nur77), an immediate-early response gene induced by TCR engagement. Nr4a1KO mice show clear quantitative defects in antigen-induced clonal deletion. The impact of the Nr4a1 deletion is not enhanced by deletion of the proapoptotic factor Bim. In addition, Nr4a1 curtails initial differentiation into the Treg lineage in TCR transgenic mice and in nontransgenic mice. Transcriptional profiling of Nr4a1KO thymocytes under selection conditions reveals that Nr4a1 activates the transcription of several targets, consistent with these diverse actions: (i) Nr4a1 partakes in the induction of Bim after TCR triggering; (ii) perhaps paradoxically, Nr4a1 positively controls several transcripts of the Treg signature, in particular Ikzf2 and Tnfrsf9; (iii) consistent with its prosurvival and metabolic role in the liver, Nr4a1 is also required for the induction by TCR of a coordinated set of enzymes of the glycolytic and Krebs cycle pathways, which we propose may antagonize Treg selection as does activation of mTOR/Akt. Thus, Nr4a1 appears to act as a balancing molecule in fate determination at a critical juncture of T-cell differentiation.