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Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry

Matthew A. Kunicki, Laura C. Amaya Hernandez, Kara L. Davis, Rosa Bacchetta and Maria-Grazia Roncarolo
J Immunol January 1, 2018, 200 (1) 336-346; DOI: https://doi.org/10.4049/jimmunol.1701025
Matthew A. Kunicki
Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA 94305;
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Laura C. Amaya Hernandez
Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA 94305;Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; and
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Kara L. Davis
Division of Hematology/Oncology, Department of Pediatrics, Stanford University, Stanford, CA 94305
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Rosa Bacchetta
Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA 94305;
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Maria-Grazia Roncarolo
Division of Stem Cell Transplantation and Regenerative Medicine, Department of Pediatrics, Stanford University, Stanford, CA 94305;Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; and
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Abstract

Human CD3+CD4+ Th cells, FOXP3+ T regulatory (Treg) cells, and T regulatory type 1 (Tr1) cells are essential for ensuring peripheral immune response and tolerance, but the diversity of Th, Treg, and Tr1 cell subsets has not been fully characterized. Independent functional characterization of human Th1, Th2, Th17, T follicular helper (Tfh), Treg, and Tr1 cells has helped to define unique surface molecules, transcription factors, and signaling profiles for each subset. However, the adequacy of these markers to recapitulate the whole CD3+CD4+ T cell compartment remains questionable. In this study, we examined CD3+CD4+ T cell populations by single-cell mass cytometry. We characterize the CD3+CD4+ Th, Treg, and Tr1 cell populations simultaneously across 23 memory T cell–associated surface and intracellular molecules. High-dimensional analysis identified several new subsets, in addition to the already defined CD3+CD4+ Th, Treg, and Tr1 cell populations, for a total of 11 Th cell, 4 Treg, and 1 Tr1 cell subsets. Some of these subsets share markers previously thought to be selective for Treg, Th1, Th2, Th17, and Tfh cells, including CD194 (CCR4)+FOXP3+ Treg and CD183 (CXCR3)+T-bet+ Th17 cell subsets. Unsupervised clustering displayed a phenotypic organization of CD3+CD4+ T cells that confirmed their diversity but showed interrelation between the different subsets, including similarity between Th1–Th2–Tfh cell populations and Th17 cells, as well as similarity of Th2 cells with Treg cells. In conclusion, the use of single-cell mass cytometry provides a systems-level characterization of CD3+CD4+ T cells in healthy human blood, which represents an important baseline reference to investigate abnormalities of different subsets in immune-mediated pathologies.

Footnotes

  • This work was supported by grants and awards to M.-G.R. from the following organizations: Alex Lemonade Stand Foundation, Emerson Collective, Rising Tide, and CureSearch. This work was also supported by a generous gift to the Stanford Center for Genetic Immune Diseases. The data were acquired using instruments in the Stanford Shared FACS Facility, obtained using National Institutes of Health S10 Shared Instrument Grant S10D016318-01.

  • The online version of this article contains supplemental material.

  • Abbreviations used in this article:

    CM
    cell culture medium
    CSM
    cell staining medium
    CyTOF
    cytometry by time-of-flight
    MST
    minimum spanning tree
    PCA
    principal component analysis
    RT
    room temperature
    Tfh
    T follicular helper
    Tr1
    T regulatory type 1
    Treg
    T regulatory.

  • Received July 17, 2017.
  • Accepted October 26, 2017.
  • Copyright © 2017 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 200 (1)
The Journal of Immunology
Vol. 200, Issue 1
1 Jan 2018
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Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry
Matthew A. Kunicki, Laura C. Amaya Hernandez, Kara L. Davis, Rosa Bacchetta, Maria-Grazia Roncarolo
The Journal of Immunology January 1, 2018, 200 (1) 336-346; DOI: 10.4049/jimmunol.1701025

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Identity and Diversity of Human Peripheral Th and T Regulatory Cells Defined by Single-Cell Mass Cytometry
Matthew A. Kunicki, Laura C. Amaya Hernandez, Kara L. Davis, Rosa Bacchetta, Maria-Grazia Roncarolo
The Journal of Immunology January 1, 2018, 200 (1) 336-346; DOI: 10.4049/jimmunol.1701025
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Print ISSN 0022-1767        Online ISSN 1550-6606