Nr4a nuclear receptors: markers and modulators of antigen receptor signaling

Bending, David; Zikherman, Julie

doi:10.1016/j.coi.2023.102285

Cited by 6 publications

(2 citation statements)

References 64 publications

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“…Moreover, Nr4a1 −/− Nr4a2 −/− Nr4a3 −/− chimeric antigen receptor (CAR) T cells show enhanced antitumor responses in a solid tumor mouse model ( 77 ). These studies suggest that Nr4a1 and the other Nr4a family genes can act as negative regulators ( 78 ). We propose that the increased expression of Nr4a1 in Nur77-GFP HI naive CD8 + cells is part of a negative feedback mechanism also associated with strong tonic TCR stimulation.…”

Section: Discussionmentioning

confidence: 99%

Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling

Eggert,

Zinzow-Kramer,

et al. 2024

Sci. Signal.

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Naive T cells experience tonic T cell receptor (TCR) signaling in response to self-antigens presented by major histocompatibility complex (MHC) in secondary lymphoid organs. We investigated how relatively weak or strong tonic TCR signals influence naive CD8 + T cell responses to stimulation with foreign antigens. The heterogeneous expression of Nur77-GFP, a transgenic reporter of tonic TCR signaling, in naive CD8 + T cells suggests variable intensities or durations of tonic TCR signaling. Although the expression of genes associated with acutely stimulated T cells was increased in Nur77-GFP HI cells, these cells were hyporesponsive to agonist TCR stimulation compared with Nur77-GFP LO cells. This hyporesponsiveness manifested as diminished activation marker expression and decreased secretion of IFN-γ and IL-2. The protein abundance of the ubiquitin ligase Cbl-b, a negative regulator of TCR signaling, was greater in Nur77-GFP HI cells than in Nur77-GFP LO cells, and Cbl-b deficiency partially restored the responsiveness of Nur77-GFP HI cells. Our data suggest that the cumulative effects of previously experienced tonic TCR signaling recalibrate naive CD8 + T cell responsiveness. These changes include gene expression changes and negative regulation partially dependent on Cbl-b. This cell-intrinsic negative feedback loop may enable the immune system to restrain naive CD8 + T cells with higher self-reactivity.

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Section: Discussionmentioning

confidence: 99%

Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling

Eggert,

Zinzow-Kramer,

et al. 2024

Sci. Signal.

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“…As for other NRs, MAPK-specific non-genomic interactions comprise the posttranslational phosphorylation of NR4A receptors, whereas non-NRs for rapid effects elicited by NR4A-specific agonists have not been described so far [66]. Consistently, mitogen-andstress-activated-protein-kinases (MSKs) downstream of ERK1/2 or p38 are required for immediate early gene transcription of the NR4A gene family by CREB/ATF-driven promoters in murine embryonic fibroblasts [67], suggesting a reciprocal regulatory loop between the NRs and MAPKs.…”

Section: Nr4a1 (Nur77) Nr4a2 (Nurr1) and Nr4a3 (Nor1)mentioning

confidence: 99%

Mitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy

Burgermeister

2023

IJMS

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The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These ligand-activated transcription factors are divided into subclasses comprising receptors for endocrine hormones, metabolic compounds (e.g., vitamins, diet), xenobiotics, and mediators released from host immune reactions such as tissue injury and inflammation. These internal and external cues place the NRSF at the frontline as sensors and translators of information from the environment towards the genome. For most of the former “orphan” receptors, physiological and synthetic ligands have been identified, opening intriguing opportunities for combination therapies with existing cancer medications. Hitherto, only preclinical data are available, warranting further validation in clinical trials in patients. The current review summarized the existing literature covering the expression and function of NRSF subclasses in human solid tumors and hematopoietic malignancies and their modulatory effects on innate (e.g., macrophages, dendritic cells) and adaptive (i.e., T cell subsets) immune cells, encouraging mechanistic and pharmacological studies in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1).

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Characterization of CD3+ T Lymphocytes in Human Coronary Thrombi with ST-segment Elevation Myocardial Infarction

Gu,

Xia,

Zhang

et al. 2024

Thromb Haemost

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Background The occurrence and development of ST-segment elevation myocardial infarction (STEMI) are accompanied by coronary atherothrombosis and occlusion, and immune responses play prominent roles in their pathogeneses. However, the causes of atherothrombosis remain elusive, and a comprehensive study of T cell-mediated immune responses in coronary thrombi from STEMI patients is lacking. Objectives The aim of this study was to determine the heterogeneity and clonality of CD3+ T lymphocytes in STEMI patients at the single-cell level. Methods Paired single-cell RNA and T cell receptor (TCR) sequencing was performed on CD3+ T lymphocytes in the coronary thrombi and peripheral blood of STEMI patients, as well as the blood from control subjects without coronary artery disease (CAD). Results Compared with those in the peripheral blood of STEMI patients, the activation, cytotoxicity, proinflammatory, and prothrombotic characteristics of CD3+ T lymphocytes in coronary thrombi were decreased, and the clonality of CD3+ T cells was increased. Compared with those from non-CAD controls, T lymphocytes from STEMI patients exhibited an upregulation of genes related to recent TCR engagement, suggesting antigen-specific stimulation in STEMI. Antigen specificity prediction using an algorithm indicated the probability of T cells from different patients binding to similar antigens for clonal expansion during STEMI. Conclusion This study provides a basis for exploring the cellular heterogeneity of CD3+ T lymphocytes in the coronary thrombi and peripheral blood of STEMI patients. Identifying the precise adaptive immune mechanisms driving atherothrombosis may lead to innovative therapies that selectively target the aberrant immune response, resulting in more effective treatments for STEMI.

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Nr4a nuclear receptors: markers and modulators of antigen receptor signaling

Cited by 6 publications

References 64 publications

Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling

Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling

Mitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy

Characterization of CD3+ T Lymphocytes in Human Coronary Thrombi with ST-segment Elevation Myocardial Infarction

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Nr4a nuclear receptors: markers and modulators of antigen receptor signaling

Cited by 6 publications

References 64 publications

Cbl-b mitigates the responsiveness of naive CD8 + T cells that experience extensive tonic T cell receptor signaling

Cbl-b mitigates the responsiveness of naive CD8 + T cells that experience extensive tonic T cell receptor signaling

Mitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy

Characterization of CD3+ T Lymphocytes in Human Coronary Thrombi with ST-segment Elevation Myocardial Infarction

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Resources

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Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling

Cbl-b mitigates the responsiveness of naive CD8 ⁺ T cells that experience extensive tonic T cell receptor signaling