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

Abstract

The nuclear orphan receptors NR4A1, NR4A2, and NR4A3 are immediate early genes that are induced by various signals. They act as transcription factors and their activity is not regulated by ligand binding and are thus regulated via their expression levels. Their expression is transiently induced in T cells by triggering of the T cell receptor following antigen recognition during both thymic differentiation and peripheral T cell responses. In this review, we will discuss how NR4A family members impact different aspects of the life of a T cell from thymic differentiation to peripheral response against infections and cancer.

Keywords: CD4 T cell; CD8 T cell; NR4A nuclear receptor; Nor1; Nur77; Nurr1; immune response; thymus.

Figure 1

Function of the NR4A family in thymocyte development. TCR stimulation induces expression of the NR4A family. In the nucleus, NR4As can regulate the expression of genes that control T cell tolerance. Additionally, NR4A family members can be exported from the nucleus where they directly regulate apoptosis through an interaction with Bcl-2.

Figure 2

NR4A family members expression and function in CD8⁺ T cells during an acute immune response. (A) Expression and role of NR4A members in CD8⁺ T cell response. Antigen recognition by naïve CD8⁺ T cells will induce a transcriptional program responsible for activation, proliferation, and differentiation and proliferation. Among the activation-induced genes are all the Nr4a transcription factors which are rapidly and transiently induced at the early effector stage. Early effector CD8⁺ T cells will further differentiate into effectors endowed with the ability to control the infection. Two main subpopulations of effectors are generated: short lived effector cells (SLEC) and memory precursor effector cells (MPEC). SLECs will die by apoptosis following pathogen clearance while MPECs will survive and differentiate into memory T cells. At the effector stage, NR4A1 was shown to either inhibit or have no effect on SLEC differentiation while NR4A3 was shown to diminish MPEC differentiation. At the memory stage, the Nr4a transcription was shown to be enriched in a particular subset of memory CD8⁺ T cells, the resident memory CD8⁺ T cells (Trm). All the NR4A family members participate in the differentiation of CD8⁺ Trm cells while only NR4A3 was shown to influence central memory CD8 T cell (Tcm) differentiation. (B) Proposed molecular mechanism by which NR4A influences effector CD8⁺ T cell differentiation. CD8⁺ T cell activation will lead to the opening of the chromatin allowing for the transcriptional activity of different transcription factors involved in CD8⁺ T cell response. Among these transcription factors are bZIPs and NR4As which bind bZIP or NBRE DNA-binding motifs. Thus, bZIP TFs will occupy their recognition motifs on DNA and will drive the transcription of the effector- and differentiation-related genes. NR4A will influence CD8⁺ T cell transcriptional response by competing with bZIPs for DNA occupancy and by directly regulating genes containing NBRE motifs. The identity of the genes directly regulated by NR4A are still unknown. This figure was created with Biorender.com.

Figure 3

NR4A involvement in CD8+ T cell exhaustion during a chronic immune response. During a chronic immune response, antigen persistence as well as inflammation milieu will induce CD8⁺ T cell exhaustion. This state is characterized by the acquisition of the expression of different inhibitory receptors (as PD-1, Tim-3 etc.), which dampens CD8⁺ T cell function to protect the organism against the chronically activated CD8⁺ T cells. CD8⁺ T cell exhaustion is accompanied by an increased transcription of Nr4a1, Nr4a2, and Nr4a3. At the molecular level, NR4A family members cooperate with NFAT and potentially other transcription factors to decrease the activity of AP-1 (bZIP family transcription factor) and increase the dysfunctional/exhaustion state of the CD8+ T cells. An effective reinvigorating therapy to reverse CD8⁺ T cell dysfunction is treatment with anti-PD-1 antibodies, which decreases the Nr4a transcription. This figure was created with Biorender.com.