Integrative scATAC-seq and scRNA-seq analyses map thymic iNKT cell development and identify Cbfβ for its commitment

Cell Discovery

Article

Ian Loveless¹  Indrani Datta¹  Kalpana Subedi²  Qijun Yi²  Tingting Liu²  Xiaojun Wu²  Jie Wang²  Congcong Yin²  Indra Adrianto³  Li Zhou⁴  Qing-Sheng Mi⁴  Derek B. Sant’Angelo⁵  Mitchell Kronenberg⁶ 

[1] Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, USA;Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, USA;Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, USA;Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, USA;Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, USA;Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, USA;Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA;Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, USA;Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, USA;Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, USA;Department of Internal Medicine, Henry Ford Health, Detroit, MI, USA;Child Health Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA;La Jolla Institute for Immunology, 9420 Athena Circle, La Jolla, CA, USA;

关键词: ;   

DOI  :  10.1038/s41421-023-00547-x

 received in 2022-07-27, accepted in 2023-03-18,  发布年份 2023

来源: Springer

【 摘 要 】

Unlike conventional αβT cells, invariant natural killer T (iNKT) cells complete their terminal differentiation to functional iNKT1/2/17 cells in the thymus. However, underlying molecular programs that guide iNKT subset differentiation remain unclear. Here, we profiled the transcriptomes of over 17,000 iNKT cells and the chromatin accessibility states of over 39,000 iNKT cells across four thymic iNKT developmental stages using single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to define their developmental trajectories. Our study discovered novel features for iNKT precursors and different iNKT subsets and indicated that iNKT2 and iNKT17 lineage commitment may occur as early as stage 0 (ST0) by two distinct programs, while iNKT1 commitments may occur post ST0. Both iNKT1 and iNKT2 cells exhibit extensive phenotypic and functional heterogeneity, while iNKT17 cells are relatively homogenous. Furthermore, we identified that a novel transcription factor, Cbfβ, was highly expressed in iNKT progenitor commitment checkpoint, which showed a similar expression trajectory with other known transcription factors for iNKT cells development, Zbtb16 and Egr2, and could direct iNKT cells fate and drive their effector phenotype differentiation. Conditional deletion of Cbfβ blocked early iNKT cell development and led to severe impairment of iNKT1/2/17 cell differentiation. Overall, our findings uncovered distinct iNKT developmental programs as well as their cellular heterogeneity, and identified a novel transcription factor Cbfβ as a key regulator for early iNKT cell commitment.

【 授权许可】

CC BY   
© The Author(s) 2023

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