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

• Published in: Frontiers in immunology Vol. 12; p. 732511
• Main Authors: Kiekens, Laura, Van Loocke, Wouter, Taveirne, Sylvie, Wahlen, Sigrid, Persyn, Eva, Van Ammel, Els, De Vos, Zenzi, Matthys, Patrick, Van Nieuwerburgh, Filip, Taghon, Tom, Van Vlierberghe, Pieter, Vandekerckhove, Bart, Leclercq, Georges
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 24-09-2021
• Subjects: Animals; Antibody-Dependent Cell Cytotoxicity; antibody-dependent cellular cytotoxicity; CD16 expression; Cell Differentiation; Cell Lineage; Chromatin Assembly and Disassembly; Coculture Techniques; EOMES; Epigenesis, Genetic; Fetal Blood - cytology; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Hematopoietic Stem Cells - immunology; Hematopoietic Stem Cells - metabolism; human NK cells; Humans; Immunology; Interferon-gamma - metabolism; K562 Cells; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Medicin och hälsovetenskap; Mice; Phenotype; Receptors, IgG - genetics; Receptors, IgG - metabolism; Receptors, KIR - genetics; Receptors, KIR - metabolism; T-BET; T-Box Domain Proteins - genetics; T-Box Domain Proteins - metabolism; transcription factors; Transcriptome; EOMES; human NK cells; NK cell biology; antibody-dependent cellular cytotoxicity; transcription factors; CD16 expression; NK cell therapy; T-BET
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.732511

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.