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

• Published in: Transplantation and cellular therapy Vol. 28; no. 1; pp. 18.e1 - 18.e10
• Main Authors: Macedo, Rodney, Pasin, Chloé, Ganetsky, Alex, Harle, David, Wang, Ximi K., Belay, Kirubel, Richman, Lee P., Huffman, Austin P., Vonderheide, Robert H., Yates, Andrew J., Porter, David L., Wang, Ying, Zhang, Yi, Reshef, Ran
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2022
• Subjects: Acute graft-versus-host disease; Allogeneic hematopoietic cell transplantation; Enhancer of Zeste Homolog 2 Protein - genetics; Epigenetic regulation; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation - adverse effects; Humans; Inhibitor of Differentiation Proteins; Neoplasm Proteins; T-cell function; Transplantation Conditioning; Transplantation, Homologous; Vitamin D; Vitamin D Deficiency; Acute graft-versus-host disease; Epigenetic regulation; Vitamin D; T-cell function; Allogeneic hematopoietic cell transplantation
• ISSN: 2666-6367; 2666-6375; 2666-6367
• DOI: 10.1016/j.jtct.2021.09.017

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.