T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells

• Main Authors: Laura Kiekens, Wouter Van Loocke, Sylvie Taveirne, Sigrid Wahlen, Eva Persyn, Els Van Ammel, Zenzi De Vos, Patrick Matthys, Filip Van Nieuwerburgh, Tom Taghon, Pieter Van Vlierberghe, Bart Vandekerckhove, Georges Leclercq
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2021-09-01
• Series: Frontiers in Immunology
• Subjects: human NK cells; transcription factors; T-BET; EOMES; CD16 expression; antibody-dependent cellular cytotoxicity
• Online Access: https://www.frontiersin.org/articles/10.3389/fimmu.2021.732511/full

T-bet and Eomes are transcription factors that are known to be important in maturation and function of murine natural killer (NK) cells. Reduced T-BET and EOMES expression results in dysfunctional NK cells and failure to control tumor growth. In contrast to mice, the current knowledge on the role of T-BET and EOMES in human NK cells is rudimentary. Here, we ectopically expressed either T-BET or EOMES in human hematopoietic progenitor cells. Combined transcriptome, chromatin accessibility and protein expression analyses revealed that T-BET or EOMES epigenetically represses hematopoietic stem cell quiescence and non-NK lineage differentiation genes, while activating an NK cell-specific transcriptome and thereby drastically accelerating NK cell differentiation. In this model, the effects of T-BET and EOMES are largely overlapping, yet EOMES shows a superior role in early NK cell maturation and induces faster NK receptor and enhanced CD16 expression. T-BET particularly controls transcription of terminal maturation markers and epigenetically controls strong induction of KIR expression. Finally, NK cells generated upon T-BET or EOMES overexpression display improved functionality, including increased IFN-γ production and killing, and especially EOMES overexpression NK cells have enhanced antibody-dependent cellular cytotoxicity. Our findings reveal novel insights on the regulatory role of T-BET and EOMES in human NK cell maturation and function, which is essential to further understand human NK cell biology and to optimize adoptive NK cell therapies.