Regulation of effector and memory CD8 + T cell differentiation: a focus on orphan nuclear receptor NR4A family, transcription factor, and metabolism

CD8 + T cells undergo rapid expansion followed by contraction and the development of memory cells after their receptors are activated. The development of immunological memory following acute infection is a complex phenomenon that involves several molecular, transcriptional, and metabolic mechanisms. As memory cells confer long-term protection and respond to secondary stimulation with strong effector function, understanding the mechanisms that influence their development is of great importance. Orphan nuclear receptors, NR4As, are immediate early genes that function as transcription factors and bind with the NBRE region of chromatin. Interestingly, the NBRE region of activated CD8 + T cells is highly accessible at the same time the expression of NR4As is induced. This suggests a potential role of NR4As in the early events post T cell activation that determines cell fate decisions. In this review, we will discuss the influence of NR4As on the differentiation of CD8 + T cells during the immune response to acute infection and the development of immunological memory. We will also discuss the signals, transcription factors, and metabolic mechanisms that control cell fate decisions. HIGHLIGHTS: Memory CD8 + T cells are an essential subset that mediates long-term protection after pathogen encounters. Some specific environmental cues, transcriptional factors, and metabolic pathways regulate the differentiation of CD8 + T cells and the development of memory cells. Orphan nuclear receptor NR4As are early genes that act as transcription factors and are highly expressed post-T cell receptor activation. NR4As influence the effector function and differentiation of CD8 + T cells and also control the development of immunological memory following acute infection.