NR4A3 controls CD8+ T cell metabolism and differentiation

Following an infection, naive CD8+ T cells expand and differentiate into two major populations of effectors: short-lived effector cells meant to die by apoptosis and memory precursor effector cells (MPECs) destined to survive as memory cells that will confer long-term protection. We postulated that the transcription factor NR4A3, a member of the orphan nuclear receptor family, whose expression is induced by TCR signalling, will regulate in vivo CD8+ T cell response. To elucidate the role of NR4A3 during CD8+ T cell response, we have adoptively transferred wild-type and Nr4a3−/− OT-I T cells (specific for the ovalbumin (OVA) peptide in the context of Kb) into naive recipients and analyzed their response following infection with a recombinant strain of Listeria monocytogenes encoding OVA. Although Nr4a3+/+ and Nr4a3−/− OT-I T cells expanded similarly, we observed an increased generation of MPECs at the peak of the T cell response, which led to an enhanced (2–3X) generation of memory T cells. Furthermore, Nr4a3−/− effector and memory T cells produce more cytokines than their wild-type counterpart. The analysis of the early T cell response demonstrated that NR4A3 controls the metabolic activity of activated T cells, as Nr4a3−/− OT-I T cells express less nutrient receptors and have reduced phosphorylation of S6. Altogether, these results suggest that NR4A3 controls effector and memory T cell differentiation by modulating their metabolic activity during the immune response.