Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology

Odagiu, Livia; May, Julia; Boulet, Salix; Baldwin, Troy A.; Labrecque, Nathalie

doi:10.3389/fendo.2020.624122

Cited by 62 publications

(72 citation statements)

References 133 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found upregulation of genes such as EGR1 and NR4A1 (Data S2 ) in later stages as shown in cluster 3 and is known to be induced by TCR stimulation and enhance T cell functions. 23 , 24 Genes expression in cluster 2 decreases with time, and one enriched gene set contains genes downregulated with PTEN knockdown, and PTEN was demonstrated with function promoting type 1 interferon responses and antiviral innate immunity. 25 Meanwhile, we found that type 1 interferon (IFN-I)-related genes, ISG15 , MX1 , and XAF1 , expressed more severe and moderate patients at the early stage (Fig.…”

Section: Resultsmentioning

confidence: 99%

Single-cell immune profiling reveals distinct immune response in asymptomatic COVID-19 patients

Zhao

You

Cui

et al. 2021

Sig Transduct Target Ther

View full text Add to dashboard Cite

While some individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present mild-to-severe disease, many SARS-CoV-2-infected individuals are asymptomatic. We sought to identify the distinction of immune response between asymptomatic and moderate patients. We performed single-cell transcriptome and T-cell/B-cell receptor (TCR/BCR) sequencing in 37 longitudinal collected peripheral blood mononuclear cell samples from asymptomatic, moderate, and severe patients with healthy controls. Asymptomatic patients displayed increased CD56briCD16− natural killer (NK) cells and upregulation of interferon-gamma in effector CD4+ and CD8+ T cells and NK cells. They showed more robust TCR clonal expansion, especially in effector CD4+ T cells, but lack strong BCR clonal expansion compared to moderate patients. Moreover, asymptomatic patients have lower interferon-stimulated genes (ISGs) expression in general but large interpatient variability, whereas moderate patients showed various magnitude and temporal dynamics of the ISGs expression across multiple cell populations but lower than a patient with severe disease. Our data provide evidence of different immune signatures to SARS-CoV-2 in asymptomatic infections.

show abstract

Section: Resultsmentioning

confidence: 99%

Single-cell immune profiling reveals distinct immune response in asymptomatic COVID-19 patients

Zhao

You

Cui

et al. 2021

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…Since both 1:1 and 1:5 DKO chimeras harbor 4-to 6-fold more CD4SP and CD8SP DKO cells relative to WT cells when normalized to the pre-selection DP compartment (Figure 2E), we propose that NR4A-dependent deletion may account for most or all negative selection. Prior studies implicate the NR4A family in negative selection by both ubiquitous and tissue-restricted antigens (TRA) (22,24,(48)(49)(50).…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies implicate the NR4A family in negative selection by both ubiquitous and tissue-restricted antigens (TRAs; refs. 22 , 24 , 48 – 50 ). Though our data do not directly distinguish between the two, the striking amplitude of rescue seen in DKO chimeras suggests escape from negative selection by ubiquitous self-antigens (proposed to account for 75% of all deletion) and possibly TRAs as well, but this remains to be determined ( 47 , 51 ).…”

Section: Discussionmentioning

confidence: 99%

NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity

Hiwa¹,

Nielsen²,

Mueller³

et al. 2021

JCI Insight

View full text Add to dashboard Cite

The NR4A family of orphan nuclear receptors (Nr4a1-3) plays redundant roles to establish and maintain Treg identity; deletion of multiple family members in the thymus results in Treg deficiency and a severe inflammatory disease. Consequently, it has been challenging to unmask redundant functions of the NR4A family in other immune cells.Here we use a competitive bone marrow chimera strategy, coupled with conditional genetic tools, to rescue Treg homeostasis and unmask such functions. Unexpectedly, chimeras harboring Nr4a1 -/-Nr4a3 -/-(DKO) bone marrow develop autoantibodies and a systemic inflammatory disease despite a replete Treg compartment of largely wild-type origin. This disease differs qualitatively from that seen with Treg-deficiency and is B cellextrinsic. 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 T cells with functional, phenotypic, and transcriptional features of anergy accumulate in chimeric mice. Nevertheless, we observe upregulation of genes encoding inflammatory mediators in anergic DKO T cells, and DKO T cells exhibit enhanced capacity for IL-2 production. These studies reveal cell-intrinsic roles for the NR4A family in both central and peripheral T cell tolerance, and demonstrate that each is essential to preserve immune homeostasis.(memory) compartment and upregulate well-established markers of anergy (CD73 and FR4) in a cell-intrinsic manner (Figures 6D-G) (39). Similarly, expansion of anergic CD4 + T cells was exaggerated in 1:1 DKO:WT chimeras relative to both control chimeras and SKO mice (Supplementary Figures 6A-H). Moreover, even phenotypically 'naive' DKO CD44 lo CD62L hi CD4 + T cells in mixed chimeras upregulated CD73 and FR4, suggestive of antigen encounter (Figure 6D, E, Supplementary

show abstract

“…The differences in CD8 + and CD4 + T cells, or the epigenetic profiles of exhausted versus tolerized/anergic T cells, might be a potential causative factor. Indeed, TOX and NR4A cooperatively enhance the expression of checkpoint molecules in exhausted T cells, whereas anergic T cells express NR4A without TOX [ 134 , 137 ]. Thus, the distinct regulation of checkpoint molecule expression seems to be one of the reasons for the differences in T cell motility induced by PD-1 blockade.…”

Section: Immune Checkpoint Inhibition and T Cell Motilitymentioning

confidence: 99%

Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade

Kanda

Okazaki

Katakai

2021

Cancers

View full text Add to dashboard Cite

The migration status of T cells within the densely packed tissue environment of lymph nodes reflects the ongoing activation state of adaptive immune responses. Upon encountering antigen-presenting dendritic cells, actively migrating T cells that are specific to cognate antigens slow down and are eventually arrested on dendritic cells to form immunological synapses. This dynamic transition of T cell motility is a fundamental strategy for the efficient scanning of antigens, followed by obtaining the adequate activation signals. After receiving antigenic stimuli, T cells begin to proliferate, and the expression of immunoregulatory receptors (such as CTLA-4 and PD-1) is induced on their surface. Recent findings have revealed that these ‘immune checkpoint’ molecules control the activation as well as motility of T cells in various situations. Therefore, the outcome of tumor immunotherapy using checkpoint inhibitors is assumed to be closely related to the alteration of T cell motility, particularly in tumor-draining lymph nodes (TDLNs). In this review, we discuss the migration dynamics of T cells during their activation in TDLNs, and the roles of checkpoint molecules in T cell motility, to provide some insight into the effect of tumor immunotherapy via checkpoint blockade, in terms of T cell dynamics and the importance of TDLNs.

show abstract

Role of the Orphan Nuclear Receptor NR4A Family in T-Cell Biology

Cited by 62 publications

References 133 publications

Single-cell immune profiling reveals distinct immune response in asymptomatic COVID-19 patients

Single-cell immune profiling reveals distinct immune response in asymptomatic COVID-19 patients

NR4A family members regulate T cell tolerance to preserve immune homeostasis and suppress autoimmunity

Motility Dynamics of T Cells in Tumor-Draining Lymph Nodes: A Rational Indicator of Antitumor Response and Immune Checkpoint Blockade

Contact Info

Product

Resources

About