The transcription factor Bach2 negatively regulates murine natural killer cell maturation and function

Abstract

BTB domain And CNC Homolog 2 (Bach2) is a transcription repressor that actively participates in T and B lymphocyte development, but it is unknown if Bach2 is also involved in the development of innate immune cells, such as natural killer (NK) cells. Here, we followed the expression of Bach2 during murine NK cell development, finding that it peaked in immature CD27+CD11b+ cells and decreased upon further maturation. Bach2 showed an organ and tissue-specific expression pattern in NK cells. Bach2 expression positively correlated with the expression of transcription factor TCF1 and negatively correlated with genes encoding NK effector molecules and those involved in the cell cycle. Lack of Bach2 expression caused changes in chromatin accessibility of corresponding genes. In the end, Bach2-deficiency resulted in increased proportions of terminally differentiated NK cells with increased production of granzymes and cytokines. NK cell-mediated control of tumor metastasis was also augmented in the absence of Bach2. Therefore, Bach2 is a key checkpoint protein regulating NK terminal maturation.

CITE-seq analysis reveals human cytomegalovirus and diabetes-associated adaptive NK cell alterations in cardiovascular disease

“…diabetes + (diabetes -CAD low/high vs. diabetes + CAD low/high ) patients. In line with other publications, we found a high increase in BACH2 (purple dot) expression in diabetes + cases 33,34 (Figure 1C, 1D). Yet, SPON2, CXCR3, and IFNG expression did not significantly change based on diabetes status alone.…”

“…We then assessed the NK cell SPON2/IFNG ratio in the CAD cohort patients based on CAD disease severity (combined percent stenosis of each artery segment score: I; 0-6 [n = 29], II; 30-48 [n = 13], III; 49-67.5 [n = 9, IV; 77-150 [n = 8]). The NK cell SPON2/IFNG ratio significantly increased in patients with higher disease burden (III: 49-67.5 and IV: 77-150, relative to I: 0-6 and II: [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48]. This indicates that the increased CAD stenosis is associated with a higher NK cell SPON2/IFNG ratio and reduced NK cell activation and reflect plaque accumulation and decreased inflammation.…”

Transcriptional control of ILC identity

“…For example, Eomes induced expression of the genes responsible for NK cell cytotoxicity ( FasL, GzmK, Klra8, Prf1 ) whereas T-bet induced expression of the genes which regulate responsiveness to IL-12 ( Il18r1, Il12 rβ 2, Ifnγ ) ( 31 , 36 ). Both T-bet and Eomes are positive regulators of NK cell maturation while Bach2 TF is a negative regulator of terminal differentiation of NK cells ( 29 , 30 ). The expression of Bach2 decreases in immature compared to terminally differentiated NK cells ( 29 , 30 ).…”

“…Both T-bet and Eomes are positive regulators of NK cell maturation while Bach2 TF is a negative regulator of terminal differentiation of NK cells ( 29 , 30 ). The expression of Bach2 decreases in immature compared to terminally differentiated NK cells ( 29 , 30 ). Moreover, Bach2 deficiency led to upregulation of genes responsible for NK cell effector functions such as granzyme B and KLRG1, suggesting that Bach2 can control NK cell maturation through repression of effector genes ( 30 ).…”

“…The maturation states are defined according to the group of markers that they express, such as acquiring integrin aM (CD11b) and downregulating CD27 markers (26,27). Immature NK cells (CD27 + CD11b -) develop to terminally differentiated NK cells (CD27 -CD11b + KLRG1 + ) with high cytotoxic capacity and with the ability to produce IFNg (28)(29)(30). Transcription factors Eomes and T-bet are critical for normal development and maturation of NK cells (15,31,32).…”