| 1. |
|
|
| 2. |
- Kiekens, L, et al.
(författare)
-
T-BET and EOMES Accelerate and Enhance Functional Differentiation of Human Natural Killer Cells
- 2021
-
Ingår i: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 12, s. 732511-
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 3. |
- Persyn, E, et al.
(författare)
-
TXNIP Promotes Human NK Cell Development but Is Dispensable for NK Cell Functionality
- 2022
-
Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:19
-
Tidskriftsartikel (refereegranskat)abstract
- The ability of natural killer (NK) cells to kill tumor cells without prior sensitization makes them a rising player in immunotherapy. Increased understanding of the development and functioning of NK cells will improve their clinical utilization. As opposed to murine NK cell development, human NK cell development is still less understood. Here, we studied the role of thioredoxin-interacting protein (TXNIP) in human NK cell differentiation by stable TXNIP knockdown or overexpression in cord blood hematopoietic stem cells, followed by in vitro NK cell differentiation. TXNIP overexpression only had marginal effects, indicating that endogenous TXNIP levels are sufficient in this process. TXNIP knockdown, however, reduced proliferation of early differentiation stages and greatly decreased NK cell numbers. Transcriptome analysis and experimental confirmation showed that reduced protein synthesis upon TXNIP knockdown likely caused this low proliferation. Contrary to its profound effects on the early differentiation stages, TXNIP knockdown led to limited alterations in NK cell phenotype, and it had no effect on NK cell cytotoxicity or cytokine production. Thus, TXNIP promotes human NK cell differentiation by affecting protein synthesis and proliferation of early NK cell differentiation stages, but it is redundant for functional NK cell maturation.
|
|
| 4. |
- Taveirne, S, et al.
(författare)
-
The transcription factor ETS1 is an important regulator of human NK cell development and terminal differentiation
- 2020
-
Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 136:3, s. 288-298
-
Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells are important in the immune defense against tumor cells and pathogens, and regulate other immune cells by cytokine secretion. Whereas murine NK cell biology has been extensively studied, knowledge about transcriptional circuitries controlling human NK cell development and maturation is limited. By generating ETS1-deficient human embryonic stem cells (hESC) and by expressing the dominant-negative ETS1 p27 isoform in cord blood (CB) hematopoietic progenitor cells (HPCs), we show that the transcription factor ETS1 is critically required for human NK cell differentiation. Genome-wide transcriptome analysis determined by RNA-sequencing combined with chromatin immunoprecipitation-sequencing (ChIP-seq) analysis reveals that human ETS1 directly induces expression of key transcription factors that control NK cell differentiation, i.e. E4BP4, TXNIP, TBET, GATA3, HOBIT and BLIMP1. In addition, ETS1 regulates expression of genes involved in apoptosis and NK cell activation. Our study provides important molecular insights into the role of ETS1 as an important regulator of human NK cell development and terminal differentiation.
|
|
| 5. |
|
|
| 6. |
- Van Crombruggen, K, et al.
(författare)
-
Innate lymphoid cells in the upper airways: importance of CD117 and IL-1RI expression
- 2018
-
Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 52:6
-
Tidskriftsartikel (refereegranskat)abstract
- Although type 1, 2 and 3 innate lymphoid cells (ILC1s, ILC2s and ILC3s, respectively) are emerging as important cell populations regulating tissue homeostasis, remodelling and inflammation, a vast majority of our knowledge stems from in vitro and murine experiments, and requires thorough confirmation in human diseases.Relative levels of ILCs were evaluated by means of flow cytometry in freshly resected human upper airways mucosa of patients with chronic rhinosinusitis without nasal polyps (CRSsNP) and with nasal polyps (CRSwNP), taking into account the patient's clinical parameters and disease comorbidities.We report that the CD117 and interleukin-receptor type I (IL-1RI) expression status of human ILC2s depends on the local tissue environment. Only CD117+ IL-1RI+ ILC2s, exclusively present in CRSwNP, possess an interrelationship with type 2 T-helper cell cytokine and eosinophil levels in human upper airway mucosa. In CRSsNP, mainly CD117−IL-1RI− ILC2s are increased, yielding lower eosinophilia in this disease despite the high levels of ILC2s.These data unveil that the CD117− and CD117+ fractions within the native human ILC2 population are not a random phenomenon, in contrast to what could be concluded from in vitro data, and that the IL-1RI expression is not ubiquitous in ILC2s in vivo in humans, which cannot be assessed via in vitro and murine experiments.
|
|
