Synergized regulation of NK cell education by NKG2A and specific Ly49 family members

Xiaoqian Zhang,Haoyan Yang,Shasha Chen,Zhongjun Dong,Jin Feng

doi:10.1038/s41467-019-13032-5

Xiaoqian Zhang, Haoyan Yang + Show 3 more

Open Access

https://doi.org/10.1038/s41467-019-13032-5

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Journal: Nature Communications	Publication Date: Nov 1, 2019
Citations: 43	License type: open-access

Affiliation: Tsinghua University

Abstract

Mice lacking MHC class-I (MHC-I) display severe defects in natural killer (NK) cell functional maturation, a process designated as “education”. Whether self-MHC-I specific Ly49 family receptors and NKG2A, which are closely linked within the NK gene complex (NKC) locus, are essential for NK cell education is still unclear. Here we show, using CRISPR/Cas9-mediated gene deletion, that mice lacking all members of the Ly49 family exhibit a moderate defect in NK cell activity, while mice lacking only two inhibitory Ly49 members, Ly49C and Ly49I, have comparable phenotypes. Furthermore, the deficiency of NKG2A, which recognizes non-classical MHC-Ib molecules, mildly impairs NK cell function. Notably, the combined deletion of NKG2A and the Ly49 family severely compromises the ability of NK cells to mediate “missing-self” and “induced-self” recognition. Therefore, our data provide genetic evidence supporting that NKG2A and the inhibitory members of Ly49 family receptors synergize to regulate NK cell education.

Highlights

Mice lacking MHC class-I (MHC-I) display severe defects in natural killer (NK) cell functional maturation, a process designated as “education”
The expression of MHC-I-specific receptors strongly correlates with NK-cell activity[15,30,31,32]
Using CRISPR/Cas9-mediated genome editing, we reveal that inhibitory members of Ly49 family are critical for NK-cell education, while NKG2A provides a synergistic effect with Ly49 family

Summary

Introduction

Mice lacking MHC class-I (MHC-I) display severe defects in natural killer (NK) cell functional maturation, a process designated as “education”. Our data provide genetic evidence supporting that NKG2A and the inhibitory members of Ly49 family receptors synergize to regulate NK cell education. Convincing genetic evidence that completely support the hypothesis that MHC-I molecules regulate NK-cell education via their engagement with the Ly49 family and/or NKG2A is still lacking, largely because the Ly49family members highly share sequence similarity and are closely positioned together within the NK-cell gene complex (NKC) on chromosome 6. Using CRISPR/Cas9-mediated genome editing, we reveal that inhibitory members of Ly49 family are critical for NK-cell education, while NKG2A provides a synergistic effect with Ly49 family. This finding will help to understand the mechanism underpinning NK-cell tolerance

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Conclusion