Programmed differentiated natural killer cells kill leukemia cells by engaging SLAM family receptors.

Yang Wu,Aimei Zhang,Zhigang Tian,Linlin Jin,Binqing Fu,Rui Sun,Haiming Wei,Young Li,Xiaohu Zheng

doi:10.18632/oncotarget.18659

Abstract

Natural killer (NK) cells are important innate immune cells that can directly kill transformed or virus-infected cells. The adoptive transfer of NK cells has been used to treat hematological malignancies; however, the limited sources and quantities of NK cells have restricted their clinical application. Here, we acquired sufficient quantities of functional NK cells from CD34+ cells treated with a cytokine cocktail. Microarray analysis of the cultured cells revealed a two-stage pattern of programmed differentiation during NK cell development. Different transcription factors were enriched during these two stages, suggesting that preparation of progenitors committed to the NK cell lineage occurs in program 1, while NK cell transformation and maturation occur in program 2. Cultured NK cells highly expressed signaling lymphocytic activation molecule (SLAM) family receptors (SFRs), while leukemia cells expressed SFR ligands. The engagement of these SFRs strengthened the cytotoxicity of NK cells toward leukemia cells. These results demonstrate a simple method of obtaining sufficient NK cells for clinical application, and have categorized NK cell differentiation according to commitment and transformation programs. Moreover, the binding between SFRs on NK cells and their ligands on leukemia cells suggests a new basis for NK cell therapy for treatment of leukemia.

Highlights

Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) that are differentiated from T-bet+ ILC1, GATA binding protein 3 (GATA-3)+ ILC2 and RAR-related orphan receptor gamma (RORγ)t+ ILC3 cells [1]
Cultured NK cells highly expressed signaling lymphocytic activation molecule (SLAM) family receptors (SFRs), while leukemia cells expressed SLAM family receptors (SFRs) ligands. The engagement of these SFRs strengthened the cytotoxicity of NK cells toward leukemia cells. These results demonstrate a simple method of obtaining sufficient NK cells for clinical application, and have categorized NK cell differentiation according to commitment and transformation programs
The flt3 ligand and c-kit ligand can induce the expression of IL-2/15Rβ (CD122) and increase IL15Rα transcripts in CD34+ hematopoietic progenitor cells to promote their response to IL-15 [19], which is indispensable for NK cell development and activation [20, 21]

Summary

Introduction

Natural killer (NK) cells are cytotoxic innate lymphoid cells (ILCs) that are differentiated from T-bet+ ILC1, GATA binding protein 3 (GATA-3)+ ILC2 and RAR-related orphan receptor gamma (RORγ)t+ ILC3 cells [1]. The differentiation of NK cells consists of four stages in vivo, and is characterized by the surface expression of CD34, CD117 and CD94 [3]. During NK cell development, transcription factors (TFs) promote NK cell commitment and impart corresponding cellular functions. T-bet, Eomesodermin (Eomes), ETS1, inhibitor of DNA binding 2 (ID2), thymocyte selection-associated HMG-box protein (TOX), TOX2, nuclear factor, interleukin 3 regulated (NFIL3/E4BP4) and forkhead box protein O1 (FOXO1) regulate NK cell development and maturation in distinct stages [4,5,6,7,8,9,10,11]. The precise hierarchy by which these known TFs regulate NK cell development is not fully understood

Methods

Results

Conclusion