Single-cell transcriptomic analysis reveals disparate effector differentiation pathways in human Treg compartment

Yuechen Luo, Changlu Xu, Bing Wang, Qing Niu, Xiuhua Su, Yingnan Bai, Shuxian Zhu, Chunxiao Zhao, Yunyan Sun, Jiali Wang, Maolan Liu, Xiaolei Sun, Ge Song, Haidong Cui, Xiaoli Chen, Huifang Huang, Haikun Wang, Mingzhe Han (), Erlie Jiang (), Lihong Shi () and Xiaoming Feng ()
Additional contact information
Yuechen Luo: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Changlu Xu: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Bing Wang: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Qing Niu: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Xiuhua Su: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Yingnan Bai: Novogene Co., Ltd.
Shuxian Zhu: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Chunxiao Zhao: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Yunyan Sun: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Jiali Wang: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Maolan Liu: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Xiaolei Sun: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Ge Song: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Haidong Cui: Hangzhou First People’s Hospital
Xiaoli Chen: the Affiliated Ganzhou Hospital of Nanchang University
Huifang Huang: Fujian Medical University Union Hospital
Haikun Wang: Institut Pasteur of Shanghai, Chinese Academy of Sciences
Mingzhe Han: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Erlie Jiang: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Lihong Shi: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Xiaoming Feng: Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Human FOXP3+ regulatory T (Treg) cells are central to immune tolerance. However, their heterogeneity and differentiation remain incompletely understood. Here we use single-cell RNA and T cell receptor sequencing to resolve Treg cells from healthy individuals and patients with or without acute graft-versus-host disease (aGVHD) who undergo stem cell transplantation. These analyses, combined with functional assays, separate Treg cells into naïve, activated, and effector stages, and resolve the HLA-DRhi, LIMS1hi, highly suppressive FOXP3hi, and highly proliferative MKI67hi effector subsets. Trajectory analysis assembles Treg subsets into two differentiation paths (I/II) with distinctive phenotypic and functional programs, ending with the FOXP3hi and MKI67hi subsets, respectively. Transcription factors FOXP3 and SUB1 contribute to some Path I and Path II phenotypes, respectively. These FOXP3hi and MKI67hi subsets and two differentiation pathways are conserved in transplanted patients, despite having functional and migratory impairments under aGVHD. These findings expand the understanding of Treg cell heterogeneity and differentiation and provide a single-cell atlas for the dissection of Treg complexity in health and disease.

Date: 2021
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DOI: 10.1038/s41467-021-24213-6

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