NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance*

Abstract

The Achilles heel of the adaptive immune system is certainly the risk of mounting destructive and often durable immune responses directed toward self-antigens. As a testament to this risk, a broad array of distinct human autoimmune diseases has been defined, ranging from the tissue-specific to the systemic; these include well-recognized entities such as type I diabetes, multiple sclerosis, and systemic lupus erythematosus, and extend to diseases like myasthenia gravis and Graves' disease with highly specific and focused target antigens. In addition, the risk of triggering frank autoimmunity is a dark shadow that can trail otherwise protective immune responses to cancer neo-antigens in the form of paraneoplastic syndromes, and to infectious diseases via molecular mimicry (eg, rheumatic fever and Guillain-Barré syndrome). Most recently, release of latent auto-reactivity triggered by therapeutic checkpoint blockade has manifested in the form of occasionally severe immune-related adverse events (irAEs). Therefore, it should come

Many Achilles’ heels of B and T cell tolerance

“…Zikherman and colleagues review recent work from the labs of Chen Dong and Anjana Rao that reveal a key role for the NR4A family in regulation of the transcriptional and epigenetic landscape of tolerant T cells (both in exhausted and anergic T cells, collectively termed by some as "dysfunctional" T cells). 1 These studies show that following chronic Ag stimulation, T cells alter their epigenetic landscape to increase the accessibility of NFAT and NR4A motifs, while NR4A-deficient T cells exhibit increased accessibility of NFAT-AP1 and NF-κB sites. Moreover, NR4A overexpression induces a tolerogenic transcriptional program, while NR4A-deficient T cells inappropriately express effector cytokines and evade tolerance and exhaustion.…”

“…During T cell development, recognition of either ubiquitous or tissue‐specific antigens presented by specialized cell populations in the thymus can either drive self‐reactive thymocytes into clonal deletion or divert them into the regulatory T cell (Treg) lineage. Zikherman and colleagues review work from many groups over three decades describing an essential role for the NR4A family of orphan nuclear receptors in these processes 1 . The NR4A family members are immediate early genes that are rapidly induced by antigen receptor stimulation and their expression scales with both the intensity and duration of signaling.…”

“…Although the requirement for a second signal for B cell responses has been long appreciated, as has the molecular basis of such signals, it has been less clear what factors constrain B cells that receive signal 1 in the absence of signal 2. Zikherman and colleagues recently described a role for the NR4A family that helps to enforce B cell dependence upon second signals, thus limiting inappropriate responses to self‐antigens 1 . They uncovered a transcriptional negative feedback loop triggered by BCR stimulation and mediated by the NR4A family that restrains upregulation of a small subset of key primary response genes, including Batf and Myc .…”

“…These include genes that encode inhibitory co‐receptors, ubiquitin ligases, and other negative regulators of TCR signaling, as well as a core set of transcription factors (TFs). Zikherman and colleagues review recent work from the labs of Chen Dong and Anjana Rao that reveal a key role for the NR4A family in regulation of the transcriptional and epigenetic landscape of tolerant T cells (both in exhausted and anergic T cells, collectively termed by some as “dysfunctional” T cells) 1 . These studies show that following chronic Ag stimulation, T cells alter their epigenetic landscape to increase the accessibility of NFAT and NR4A motifs, while NR4A‐deficient T cells exhibit increased accessibility of NFAT‐AP1 and NF‐κB sites.…”

Therapeutic potential of NR4A1 in cancer: Focus on metabolism

“…NR4A1 is an immediate gene induced by stress, cytokines, growth factor, glucose, fatty acids, or other stimuli (18)(19)(20)(21). NR4A1 plays diverse roles in many physiological and pathological processes, for example cell survival, apoptosis, differentiation, cell cycle, inflammation, immunity, and metabolism (22)(23)(24)(25)(26). NR4A1 can bind to DNA in three ways to regulate the expression of target genes: (1) it can form the response element NBRE (sequence: AAAGGTCA); (2) it FIGURE 1 binds to the NurRE element (AAAT(G/A)(C/T)CA, which are related to the NBRE) in the form of homodimer or heterodimer formed with other members of the family; (3) NR4A1 and retinoid X receptors (RXRs) form heterodimers and then binds to the DR5 response element to produce transcriptional activation (sequence: AGGTCA-NNNAA-AGGTCA) (27) (Figure 2).…”