Development of Natural Killer Cells Regulated by T-Box Transcription Factors

Natural killer (NK) cells play critical roles in host defense against tumors and intracellular pathogens. Various transcription factors have been reported to alter NK cell development, but the definitive transcriptional program governing this process is not well understood. Our laboratory has shown previously that the T-box transcription factors T-bet and Eomesodermin (Eomes) direct fate and function in cytotoxic T lymphocytes. We thus endeavored to define the roles of T-bet and Eomes in the differentiation of NK cells. We find that NK progenitor cells give rise to immature-phenotype NK cells, which express the death ligand TRAIL and the transcription factor T-bet but lack a combinatorial repertoire of activating and inhibitory Ly49 molecules, responsible for the broad specificity of NK cells against microbial components and missing self. T-bet appears essential to stabilize this immature lineage. Immature NK cells give rise to mature NK cells that express the integrin CD49b (DX5+) and a diverse repertoire of Ly49 family receptors. Mature NK cells maintain expression of T-bet and induce expression of Eomes. T-bet is dispensable for the development of mature NK cells. Eomes, however, is critical for the development of mature NK cells. Eomes also maintains aspects of the mature phenotype. The effects of T-bet deletion and Eomes deletion are complementary and additive, as no NK cells are observed in mice lacking both T-bet and Eomes. The biological basis for stepwise maturation of NK cells appears to rest in a strict prohibition against induction of Eomes until post-natal life. Restriction of Eomes expression by fetal and adult liver limits NK development to a T-bet-dependent, immature state, whereas medullary hematopoiesis is permissive for Eomes induction and progression to NK cell maturity. These findings reveal critical, genetically separable checkpoints in maturation of NK cells.