SRC-3 functions as a coactivator of T-bet by regulating the maturation and antitumor activity of natural killer cells.

Natural killer (NK) cell development and maturation is a well-organized process. The steroid receptor coactivator 3 (SRC-3) is a regulator of the hematopoietic and immune systems; however, its role in NK cells is poorly understood. Here, SRC-3 displayed increased nuclear translocation in NK cells during terminal differentiation and upon inflammatory cytokine stimulation. Targeted deletion of SRC-3 altered normal NK cell distribution and compromised NK cell maturation. SRC-3 deficiency led to significantly impaired NK cell functions, especially their antitumor activity. The expression of several critical T-bet target genes, including Zeb2, Prdm1 and S1pr5, but not T-bet itself, was markedly decreased in NK cells in the absence of SRC-3. There was a physiological interaction between SRC-3 and T-bet proteins, where SRC-3 was recruited by T-bet to regulate the transcription of the aforementioned genes. Collectively, our findings unmask a previously unrecognized role of SRC-3 as a coactivator of T-bet in NK cell biology and indicate that targeting SRC-3 may be a promising strategy to increase the tumor surveillance function of NK cells.