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.