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

ABSTRACT 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.