Vitamin D deficiency after allogeneic hematopoietic cell transplantation promotes T-cell activation and is inversely associated with an EZH2-ID3 signature

  • Author Footnotes
    † R.M., C.P., and A.G. contributed equally.
    Rodney Macedo
    Footnotes
    † R.M., C.P., and A.G. contributed equally.
    Affiliations
    Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
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  • Author Footnotes
    † R.M., C.P., and A.G. contributed equally.
    Chloé Pasin
    Footnotes
    † R.M., C.P., and A.G. contributed equally.
    Affiliations
    Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
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  • Author Footnotes
    † R.M., C.P., and A.G. contributed equally.
    Alex Ganetsky
    Footnotes
    † R.M., C.P., and A.G. contributed equally.
    Affiliations
    Department of Pharmacy, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania
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  • David Harle
    Affiliations
    Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
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  • Ximi K. Wang
    Affiliations
    Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
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  • Kirubel Belay
    Affiliations
    Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
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  • Lee P. Richman
    Affiliations
    Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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  • Austin P. Huffman
    Affiliations
    Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York

    Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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  • Robert H. Vonderheide
    Affiliations
    Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania

    Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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  • Andrew J. Yates
    Affiliations
    Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York
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  • David L. Porter
    Affiliations
    Abramson Cancer Center and the Division of Hematology and Oncology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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  • Ying Wang
    Affiliations
    Fels Institute for Cancer Research and Molecular Biology, Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Yi Zhang
    Affiliations
    Fels Institute for Cancer Research and Molecular Biology, Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, Pennsylvania
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  • Ran Reshef
    Correspondence
    Correspondence and reprint requests: Ran Reshef, MD, Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, New York, NY 10032.
    Affiliations
    Columbia Center for Translational Immunology, Department of Medicine, Columbia University Irving Medical Center, New York, New York
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  • Author Footnotes
    † R.M., C.P., and A.G. contributed equally.
Published:September 28, 2021DOI:https://doi.org/10.1016/j.jtct.2021.09.017

      Abstract

      Vitamin D promotes a shift from a proinflammatory to a more tolerogenic immune state in allogeneic hematopoietic cell transplant (HCT) recipients. The dominant mechanism responsible for this shift has not been elucidated. We took a multifaceted approach to evaluating the clinical and immunologic impact of low vitamin D levels in 53 HCT recipients. We used 28-plex flow cytometry for immunophenotyping, serum cytokine levels, T-cell cytokine production, and T-cell whole genome transcription. The median day-30 vitamin D level was 20 ng/mL, and deficiency was common in younger patients undergoing myeloablative transplantation. Low vitamin D levels were associated with a high CD8/Treg ratio, increased serum levels and T-cell production of proinflammatory cytokines, and a gene expression signature of unrestrained T-cell proliferation and epigenetic modulation through the PRC2/EZH2 complex. Immunophenotyping confirmed a strong association between high levels of vitamin D and an activated EZH2 signature, characterized by overexpression of ID3, which has a role in effector T-cell differentiation. Our findings demonstrate the critical role of vitamin D in modulating T-cell function in human GVHD and identify a previously undescribed interaction with EZH2 and ID3, which may impact effector differentiation and has implications to cell therapies and other forms of cancer immunotherapy.
      © 20XX American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

      Key Words

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