The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation

Holmes, Tim D.; Pandey, Ram Vinay; Helm, Eric Y.; Schlums, Heinrich; Han, Hongya; Campbell, Tessa Mollie; Drashansky, Theodore T.; Chiang, Samuel C.C.; Wu, Cheng Ying; Tao, Christine; Shoukier, Moneef; Hardenberg, Sandra von; Sun, Miao; Klemann, Christian; Marsh, Rebecca; Lau, Colleen M.; Lin, Yin; Sun, Joseph C.; Månsson, Robert; Cichocki, Frank; Avram, Dorina; Bryceson, Yenan T.

doi:10.1126/sciimmunol.abc9801

Cited by 56 publications

(60 citation statements)

References 89 publications

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“…Next, we sought a transcriptional basis for the observed alteration in NK homeostasis. Several recent papers have described the transcriptome of NK cells related to differentiation stages using bulk or single-cell RNA sequencing showing a distinct profile of the immature CD56 bright NK cell subset 9,10,38 . Given the relative increase in CD56 bright NK cells in patients with perturbed NK cell homeostasis, the transcriptional profiles were compared with both bulk and sorted CD56 bright NK cells from healthy donors.…”

Section: Discussionmentioning

confidence: 99%

“…CD56 dim NK cells can be subdivided according to expression of the inhibitory receptor NKG2A, killer-immunoglobulin-like receptors (KIR) and the carbohydrate epitope CD57, which associates with changes in functionality as well as longevity 6,7,8 . Recent studies have revealed a set of regulatory gene circuits that reciprocally regulate NK cell differentiation, including TCF7-LEF1, MYC and RUNX2 associated with the early CD56 bright stage and PRDM1-ZEB2 and BCL11B associated with the CD56 dim stage and CMV-induced adaptive NK cell expansions 9,10 .…”

Section: Introductionmentioning

confidence: 99%

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

Sohlberg

Pfefferle

Ask

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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Sohlberg

Pfefferle

Ask

et al. 2022

Blood

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“…In breast cancer, CD59 could promote the growth of neoplasm and predict the poorly prognostic status ( 40 ). The transcription factor BCL11B is an important immunoregulatory factor that can promote the typical and adaptive differentiation of NK cells ( 41 ). Emerging reports have shown that BASP1 could modulate multiple biological behaviors, such as cell proliferation, apoptosis, and differentiation ( 42 , 43 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of the Immune Regulator CXCR4 as a Novel Promising Target for Gastric Cancer

Xue

Bei

et al. 2021

Front. Immunol.

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Immune checkpoint blockade has attracted a lot of attention in the treatment of human malignant tumors. We are trying to establish a prognostic model of gastric cancer (GC) based on the expression profile of immunoregulatory factor-related genes. Based on the TCGA database, we identified 234 differentially expressed immunoregulatory factors. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) conducted enrichment analysis to clarify the biological functions of differential expression of immunoregulatory factors. STRING database predicted the interaction network between 234 differently expressed immune regulatory factors. The expression of 11 immunoregulatory factors was significantly related to the overall survival of gastric cancer patients. Univariate Cox regression analysis, Kaplan–Meier analysis and multivariate Cox regression analysis found that immunomodulatory factors were involved in the progression of gastric cancer and promising biomarkers for predicting prognosis. Among them, CXCR4 was related to the low survival of GC patients and a key immunomodulatory factor in GC. Based on TCGA data, the high expression of CXCR4 in GC was positively correlated with the advanced stage and grade of gastric cancer and related to poor prognosis. Univariate analysis and multivariate analysis indicated that CXCR4 was an independent prognostic indicator for TCGA gastric cancer patients. In vitro functional studies had shown that CXCR4 promoted the proliferation, migration, and invasion of gastric cancer cells. In summary, this study has determined the prognostic value of 11 immunomodulatory factors in gastric cancer. CXCR4 is an independent prognostic indicator for gastric cancer patients, which may help to improve the individualized prognostic prediction of GC and provide candidates for the diagnosis and treatment of GC.

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“…RNA-seq analysis confirmed that upregulation of ANK pathway was evident at 6 months in the Mw group. Apart from upregulation of KLRC2 and B3GAT1 and downregulation of KLRC1, the key transcription factor in the ANK pathway, BCL11b, was persistently upregulated[41]. Downregulation of EAT-2 and PLZF further corroborated the classic gene expression signature of ANK cells.…”

Section: Discussionmentioning

confidence: 97%

Impact Of an Immune Modulator Mycobacterium-w On Adaptive Natural Killer Cells and Protection Against COVID-19

Jaiswal¹,

Arunachalam²,

Saifullah³

et al. 2021

Preprint

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SummaryThe kinetics of NKG2C+ adaptive natural killer (ANK) cells and NKG2A+inhibitory NK (iNK) cells with respect to the incidence of SARS-CoV-2 infection were studied in a cohort of health-care workers following administration of heat killed Mycobacterium w (Mw group) in comparison to a control group. COVID-19 infection correlated with a lower NKG2C+ANK cells at baseline. NKG2C+ANK cells at baseline did not differ, but there was a significant upregulation of NKG2C expression and cytokine release in the Mw group (p=0.0009), particularly in those with lower baseline NKG2C expression (<15%), along with marked downregulation of NKG2A+iNK cells (p<0.0001), and an increase in the NKG2C+ANK/NKG2A+iNK ratio. This translated to a significant reduction in COVID-19 and its severity in the Mw group. No impact was observed on T cell subsets. Mw was observed to have a salutary impact on the ANK cell profile which might have provided protection against COVID-19 over a prolonged period in a non-immune high-risk population.

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The transcription factor Bcl11b promotes both canonical and adaptive NK cell differentiation

Cited by 56 publications

References 89 publications

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

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

Identification and Validation of the Immune Regulator CXCR4 as a Novel Promising Target for Gastric Cancer

Impact Of an Immune Modulator Mycobacterium-w On Adaptive Natural Killer Cells and Protection Against COVID-19

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