Feb 22, 2012

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

Proceedings of the National Academy of Sciences of the United States of America
Marlys S FassettChristophe Benoist

Abstract

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 selec...Continue Reading

Mentioned in this Paper

Metabolic Process, Cellular
Biochemical Pathway
T-Lymphocyte
TNFRSF9 gene
Apoptosis, Intrinsic Pathway
Enzymes, antithrombotic
Transcription, Genetic
IER3 gene
Thymocyte
Gene Deletion Abnormality

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Apoptosis

Apoptosis is a specific process that leads to programmed cell death through the activation of an evolutionary conserved intracellular pathway leading to pathognomic cellular changes distinct from cellular necrosis