Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function

Vargas-Hernández, Alexander; Witalisz-Siepracka, Agnieszka; Prchal-Murphy, Michaela; Klein, Klara R.; Mahapatra, Sanjana; Al‐Herz, Waleed; Mace, Emily M.; Carisey, Alexandre F.; Sexl, Veronika; Forbes, Lisa R.

doi:10.1016/j.jaci.2019.09.016

Cited by 26 publications

(23 citation statements)

References 65 publications

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“…STAT3 mutation is the most common mutation in T-LGL, with STAT5B in rarer cases 47,48 and interestingly, STAT5B mutations have similar effects on NK cells as what is described here 49 . Whether affected NK homeostasis is a common feature of T-LGL, and associated with any particular genetic background, should be explored in a larger patient cohort, as well as in patients with T-LGL that do not display neutropenia.…”

Section: Discussionsupporting

confidence: 74%

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Sohlberg

Pfefferle

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et al. 2022

Blood

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Neutrophils have been suggested to play a critical role in terminal differentiation of NK cells. Whether this is a direct effect or a consequence of global immune changes with effects on NK cell homeostasis remains unknown. Here, we used high-resolution flow- and mass cytometry to examine NK cell repertoires in 64 patients with neutropenia and 27 healthy age- and gender-matched donors. A subgroup of patients with chronic neutropenia showed severely disrupted NK cell homeostasis manifested as increased frequencies of CD56bright NK cells and a lack of mature CD56dim NK cells. These immature NK cell repertoires were characterized by expression of proliferation/exhaustion markers Ki-67, Tim-3 and TIGIT and displayed blunted tumor target cell responses. Systems-level immune mapping revealed that the changes in immunophenotypes were confined to NK cells, leaving T cell differentiation intact. RNA sequencing of NK cells from these patients showed upregulation of a network of genes, including TNFSF9, CENPF, MKI67 and TOP2A, associated with apoptosis and the cell cycle, different from conventional CD56bright signatures. Profiling of 249 plasma proteins showed a coordinated enrichment of pathways related to apoptosis and cell turnover, which correlated with immature NK cell repertoires. Notably, most of these patients exhibited severe-grade neutropenia, suggesting that the profoundly altered NK cell homeostasis was connected to the severity of their underlying etiology. Hence, although our data suggests that neutrophils are dispensable for NK cell development and differentiation, some patients displayed a specific gap in the NK repertoire, associated with poor cytotoxic function and more severe disease manifestations.

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Section: Discussionsupporting

confidence: 74%

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Sohlberg

Pfefferle

Ask

et al. 2022

Blood

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“…The indispensable role of STAT5mediated transcriptional regulation in NK cell development has been highlighted by the finding that NK cell differentiation was abrogated at the NKp stage in Ncr1-iCreTg mice with conditionally deleted STAT5 (100). Consistently, disrupted NK cell maturation and impaired lytic function were observed in humans with STAT5b mutations (101). Therefore, STAT5 downstream of Jak kinases is essential for transducing IL-15 signaling.…”

Section: Both Hematopoietic and Non-hematopoietic Cells Promote Nk Cementioning

confidence: 68%

Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

Wang

Zhao

2021

Front. Immunol.

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Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and possess important functional properties in anti-viral and anti-tumor responses; thus, these cells have broad potential for clinical utilization. NK cells originate from hematopoietic stem cells (HSCs) through the following two independent and continuous processes: early commitment from HSCs to IL-15-responsive NK cell progenitors (NKPs) and subsequent differentiation into mature NK cells in response to IL-15. IL-15 is the most important cytokine for NK cell development, is produced by both hematopoietic and nonhematopoietic cells, and functions through a distinct delivery process termed transpresentation. Upon being transpresented to NK cells, IL-15 contributes to NK cell development via the activation of several downstream signaling pathways, including the Ras–MEK–MAPK, JAK–STAT5, and PI3K–ATK–mTOR pathways. Nonetheless, the exact role of IL-15 in NK cell development has not been discussed in a consecutive and comprehensive manner. Here, we review current knowledge about the indispensable role of IL-15 in NK cell development and address which cells produce IL-15 to support NK cell development and when IL-15 exerts its function during multiple developmental stages. Specifically, we highlight how IL-15 supports NK cell development by elucidating the distinct transpresentation of IL-15 to NK cells and revealing the downstream target of IL-15 signaling during NK cell development.

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“…Moreover, STAT5 tetramers are required for the maturation of NK cells from the iNK to the mNK state in bone marrow and spleen, as evidenced by the substantial decrease in mNK cell numbers, but normal levels of NKPs and iNK cells, in STAT5A-STAT5B tetramer-deficient double knock-in mice (68). STAT5b mutation also leads to defective human NK cell maturation and impaired lytic function (69). These observations indicate that JAK-1/3-STAT5 is critical for NK cell maturation.…”

Section: Stat5mentioning

confidence: 99%

Molecular Regulation of NK Cell Maturation

Wang

2020

Front. Immunol.

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Natural killer (NK) cells are innate lymphocytes specialized in immune surveillance against tumors and infections. To reach their optimal functional status, NK cells must undergo a process of maturation from immature to mature NK cells. Genetically modified mice, as well as in vivo and in vitro NK cell differentiation assays, have begun to reveal the landscape of the regulatory network involved in NK cell maturation, in which a balance of cytokine signaling pathways leads to an optimal coordination of transcription factor activity. An increased understanding of NK cell maturation will greatly promote the development and application of NK cell-based clinical therapy. Thus, in this review, we summarize the dynamics of NK cell maturation, describe recently identified factors involved in the regulation of the NK cell maturation process, including cytokines and transcription factors, and discuss the importance of NK cell maturation in health and disease.

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Human signal transducer and activator of transcription 5b (STAT5b) mutation causes dysregulated human natural killer cell maturation and impaired lytic function

Cited by 26 publications

References 65 publications

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Perturbed NK-cell homeostasis associated with disease severity in chronic neutropenia

Transcription Factors Associated With IL-15 Cytokine Signaling During NK Cell Development

Molecular Regulation of NK Cell Maturation

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