GATA2-TAL1-TGF-b1 axis is essential for human NK cell development 2087

Abstract Description GATA2, along with TAL1, forms a heptameric transcriptional complex. Patients with GATA2 haploinsufficiency lack immature CD56Bright NK cells, with or without a reduction in the number of mature CD56Dim NK cells. The role of GATA2-TAL1 complex during NK cell development has not been elucidated. Using scRNA-seq data from 10 patients with GATA2 mutations, we found that TAL1 target genes, including GIMAPs, are upregulated, while TGF-b1 and its downstream targets are significantly downregulated. Ectopic expression of the GATA2T354M mutant upregulated TAL1 and its target genes. Decreasing TAL1 levels in GATA2T354M-expressing cells attenuated GIMAPs expression. We establish that GATA2, occupied the TGF-b1 promoter and regulates its expression but GATA2T354M has reduced binding activity. Reduction in TGF-b1 decreased chromatin accessibility at AP-1 binding regions, leading to defective NK cell activation. In addition, TGF-b1 promoted the degradation of TAL1. Thus, an interplay of GATA2-TAL1-TGF-b1 constitutes a vital axis to control the human NK cell development. Funding Sources This work was supported in part by NIH R01 AI102893 and NCI R01 CA179363 (SM); NCI R01 CA204231 (SR); HRHM Program of MACC Fund (SM and SR); Nicholas Family Foundation (SM); Gardetto Family’s Everyday Good Foundation Inc. (S.M.), and Nan Gardetto Endowed Chair (SM), ASH predoctoral fellowship (DW), and MCW-GRIT award (DW). Topic Categories Immune Mechanisms of Human Disease (HUM)