Nur77 Is Associated With Polyfunctional Properties in Virus-Specific Human CD8⁺ T Cells

Human CD8⁺ T cells undergo significant metabolic and transcriptional shifts during activation and differentiation. The orphan nuclear receptor Nur77 plays a role in modulating these processes and has been linked to T cell dysfunction. However, few studies have addressed its role in the memory potential and functionality of human CD8⁺ T cells. Here, we evaluated the expression of Nur77 in human CD8⁺ T cells, focusing on its relationship with their differentiation profile and functionality. Our findings indicate that Nur77 is associated with an early-differentiated, T cell factor 1⁺ (TCF-1⁺) memory-like phenotype in both total and virus-specific human CD8⁺ T cells across contexts of acute resolved or chronic viral infection and vaccination. Nur77 expression was associated with cytokine polyfunctionality and increased proliferative capacity in long-lived antigen-responsive cells. Moreover, the modulation of Nur77 activity in vitro enhanced the functionality of chronic human immunodeficiency virus (HIV) and hepatitis B virus (HBV)-specific CD8⁺ T cells. These results suggest that Nur77 is associated with polyfunctional properties in virus-specific CD8⁺ T cell responses in humans. In addition, this study provides insights into novel strategies for enhancing CD8⁺ T cell functionality in settings of chronic antigen stimulation.