Eomesodermin spatiotemporally orchestrates the early and late stages of NK cell development by targeting KLF2 and T-bet, respectively

Junming He; Donglin Chen; Wei Xiong; Xinlei Hou; Yuhe Quan; Meixiang Yang; Zhongjun Dong

doi:10.1038/s41423-024-01164-8

Eomesodermin spatiotemporally orchestrates the early and late stages of NK cell development by targeting KLF2 and T-bet, respectively

Cell Mol Immunol. 2024 May 13. doi: 10.1038/s41423-024-01164-8. Online ahead of print.

Authors

Junming He^{1

2}, Donglin Chen², Wei Xiong², Xinlei Hou², Yuhe Quan², Meixiang Yang^{3

4}, Zhongjun Dong^{5

6

7

8

9}

Affiliations

¹ The First Affiliated Hospital of Anhui Medical University and Institute for Clinical Immunology, Anhui Medical University, Anhui, 230032, China.
² State Key Laboratory of Membrane Biology, School of Medicine and Institute for Immunology, Tsinghua University, 100084, Beijing, China.
³ Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Institute of Translational Medicine, Zhuhai People's Hospital Affiliated with Jinan University, Jinan University, Zhuhai, 519000, China. mxyang@jnu.edu.cn.
⁴ The Biomedical Translational Research Institute. Key Laboratory of Ministry of Education for Viral Pathogenesis & Infection Prevention and Control (Jinan University). Guangzhou Key Laboratory for Germ-Free Animals and Microbiota Application. School of Medicine. Jinan University, Guangzhou, 510632, China. mxyang@jnu.edu.cn.
⁵ The First Affiliated Hospital of Anhui Medical University and Institute for Clinical Immunology, Anhui Medical University, Anhui, 230032, China. dongzj@mail.tsinghua.edu.cn.
⁶ State Key Laboratory of Membrane Biology, School of Medicine and Institute for Immunology, Tsinghua University, 100084, Beijing, China. dongzj@mail.tsinghua.edu.cn.
⁷ Innovative Institute of Tumor Immunity and Medicine (ITIM), Hefei, 230032, China. dongzj@mail.tsinghua.edu.cn.
⁸ Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy, Hefei, 230032, China. dongzj@mail.tsinghua.edu.cn.
⁹ Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, 230032, China. dongzj@mail.tsinghua.edu.cn.

PMID: 38740922
DOI: 10.1038/s41423-024-01164-8

Abstract

Eomesodermin (Eomes) is a critical factor in the development of natural killer (NK) cells, but its precise role in temporal and spatial coordination during this process remains unclear. Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development. Specifically, the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2, another important transcription factor. ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence (CNS) of Klf2. Utilizing the CHimeric IMmune Editing (CHIME) technique, we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest. Moreover, constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency. Conversely, Ncr1-Cre-mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27⁺CD11b⁺ phenotype to the CD27^-CD11b⁺ phenotype. Late-stage deficiency of Eomes led to a significant increase in T-bet expression, which subsequently increased the expression of the transcription factor Zeb2. Genetic deletion of one allele of Tbx21, encoding T-bet, effectively reversed the aberrant differentiation of Eomes-deficient NK cells. In summary, we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.

Keywords: Development; Eomesodermin; KLF2; Natural killer cells; T-bet.

Abstract

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