# Regulation of CD4 T cell tolerance by the NR4A family of nuclear receptors

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $587,774

## Abstract

Project Summary/Abstract
This proposal’s long-term goal is to take advantage of the biology of the NR4A family of orphan nuclear hormone
receptors to selectively manipulate antigen-specific T cell responses in immune-mediated diseases.
NR4A members (NUR77, NURR1, and NOR1) are encoded by three genes (Nr4a1-3, respectively) that are
rapidly induced by antigen (Ag) stimulation in lymphocytes. Although they are thought to function as ligand-
independent, constitutively active transcription factors, small molecule agonist and antagonist ligands have been
developed, rendering them druggable. We and others have shown that NR4A TF expression scales with the
intensity of Ag stimulation, and are highly upregulated in thymocytes undergoing negative selection, in regulatory
T cells (Tregs), as well as in self-reactive, anergic, or exhausted T cells. Due to an overlapping expression pattern
and considerable structural homology in their DNA-binding domain, the NR4A TFs exhibit profound functional
redundancy; thymic deletion of multiple - but not individual - NR4A family members (Nr4a1 and Nr4a3 >> Nr4a2,
which is minimally expressed) results in severe Treg deficiency and a “scurfy-like” disease that phenocopies
Foxp3-/- mice. Consequently, it has not been possible previously to unmask additional redundant functions of
this family during thymic selection and in conventional mature CD4 T cells (Tconv). This represents a major gap
in our knowledge that limits full therapeutic exploitation of these factors.
Recently, we took advantage of both conditional genetic and bone marrow chimera strategies in order to preserve
Treg homeostasis. Unexpectedly, mixed chimeras harboring both WT and Nr4a1-/- Nr4a3-/- (DKO) bone marrow
rapidly develop anti-nuclear autoantibodies (ANAs) and a systemic inflammatory disease despite a replete Treg
compartment of largely WT origin. This disease differs qualitatively from that seen in germline DKO mice with
Treg-deficiency, and is B cell-extrinsic. We show that negative selection of DKO thymocytes is profoundly
impaired in a cell-intrinsic manner. Consistent with escape of self-reactive T cells into the periphery, DKO CD4
Tconv cells expressing phenotypic and transcriptional markers of anergy accumulate in these chimeras.
However, these self-reactive DKO cells nevertheless exhibit exaggerated proliferation and IL-2 production,
suggesting that functional anergy is defective. We therefore hypothesize that the NR4A family play cell-intrinsic,
but redundant, roles in both central and peripheral CD4 T cell tolerance. To test this hypothesis:
In our first aim, we propose to define the role of the NR4A family in thymic negative selection in the face of both
ubiquitous and tissue-restricted antigens, and to define the transcriptional targets that contribute to this function.
In our second aim, we propose to isolate NR4A contributions to peripheral T cell tolerance, and to canonical
features of mature CD4 T cell anergy - including impaired sig...

## Key facts

- **NIH application ID:** 10880718
- **Project number:** 5R01AI165706-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** JULIE ZIKHERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $587,774
- **Award type:** 5
- **Project period:** 2022-09-19 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880718

## Citation

> US National Institutes of Health, RePORTER application 10880718, Regulation of CD4 T cell tolerance by the NR4A family of nuclear receptors (5R01AI165706-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10880718. Licensed CC0.

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