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

Rodney Macedo, Chloé Pasin, Alex Ganetsky, David Harle, Ximi K. Wang, Kirubel Belay, Lee P. Richman, Austin P. Huffman, Robert H. Vonderheide, Andrew J. Yates, David L. Porter, Ying Wang, Yi Zhang, Ran Reshef

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)18.e1-18.e10
JournalTransplantation and Cellular Therapy
Volume28
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • Acute graft-versus-host disease
  • Allogeneic hematopoietic cell transplantation
  • Epigenetic regulation
  • T-cell function
  • Vitamin D

ASJC Scopus subject areas

  • Immunology and Allergy
  • Molecular Medicine
  • Hematology
  • Cell Biology
  • Transplantation

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