Nr4a1 and Nr4a3 redundantly control clonal deletion and contribute to an anergy-like transcriptome in auto-reactive thymocytes to impose tolerance in mice

Hailyn V. Nielsen, Letitia Yang, James L. Mueller, Alexander J. Ritter, Ryosuke Hiwa, Irina Proekt, Elze Rackaityte, Dominik Aylard, Mansi Gupta, Christopher D. Scharer, Mark S. Anderson, Byron B. Au-Yeung () and Julie Zikherman ()
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Hailyn V. Nielsen: University of California
Letitia Yang: University of California
James L. Mueller: University of California
Alexander J. Ritter: University of California
Ryosuke Hiwa: Sakyo-ku
Irina Proekt: University of California
Elze Rackaityte: University of California
Dominik Aylard: University of California
Mansi Gupta: Emory University
Christopher D. Scharer: Emory University
Mark S. Anderson: University of California
Byron B. Au-Yeung: Emory University
Julie Zikherman: University of California

Nature Communications, 2025, vol. 16, issue 1, 1-22

Abstract: Abstract The Nr4a nuclear hormone receptors are transcriptionally upregulated in response to antigen recognition by the T cell receptor (TCR) in the thymus and are implicated in clonal deletion, but the mechanisms by which they operate are not clear. Moreover, their role in central tolerance is obscured by redundancy among the Nr4a family members and by their reported functions in Treg generation and maintenance. Here we take advantage of competitive bone marrow chimeras and the OT-II/RIPmOVA model to show that Nr4a1 and Nr4a3 are essential for the upregulation of Bcl2l11/BIM and thymic clonal deletion by self-antigen. Importantly, thymocytes lacking Nr4a1/3 acquire an anergy-like signature after escaping clonal deletion and Treg lineage diversion. We further show that the Nr4a family helps mediate a broad transcriptional program in self-reactive thymocytes that resembles anergy and may operate at the margins of canonical thymic tolerance mechanisms to restrain self-reactive T cells after thymic egress.

Date: 2025
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DOI: 10.1038/s41467-025-55839-5

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