Vitamin C stabilizes CD8+ iTregs and enhances their therapeutic potential in controlling murine GVHD and leukemia relapse. Blood Adv 2019 Dec 23;3(24):4187-4201
Date
12/20/2019Pubmed ID
31856270Pubmed Central ID
PMC6929397DOI
10.1182/bloodadvances.2019000531Scopus ID
2-s2.0-85077917688 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
Adoptive transfer of induced regulatory T cells (iTregs) can ameliorate graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT). CD4+ iTregs can effectively prevent GVHD but impair the graft-versus-leukemia (GVL) effect, whereas CD8+ iTregs preserve the GVL effect but have limited efficacy in GVHD control because of their instability under inflammatory conditions. Thus, we aimed to stabilize CD8+ iTregs via treatment with vitamin C (Vit C) to improve their efficacy in controlling GVHD. We found that addition of Vit C significantly improved the stability of forkhead box P3 (Foxp3) expression in CD8+ iTregs. Moreover, Vit C-treated CD8+ iTregs exhibited high efficacy in attenuating acute and chronic GVHD. The mechanistic study revealed that addition of Vit C to CD8+ iTreg culture markedly increased DNA demethylation in the conserved noncoding sequence 2 region and, hence, maintained higher Foxp3 expression levels compared with untreated controls. In acute GVHD, Vit C-treated CD8+ iTregs were able to inhibit pathogenic T-cell expansion and differentiation while reducing thymus damage and B-cell activation in cGVHD. Importantly, in contrast to CD4+ iTregs, Vit C-treated CD8+ iTregs retained the ability to control tumor relapse. These results provide a strong rationale to use Vit C in the clinic to stabilize CD8+ iTregs for the control of GVHD and preservation of GVL after allo-HCT.
Author List
Iamsawat S, Tian L, Daenthanasanmak A, Wu Y, Nguyen HD, Bastian D, Yu XZAuthors
Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of WisconsinXue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
Adoptive TransferAnimals
Ascorbic Acid
Biomarkers
CD8-Positive T-Lymphocytes
DNA Methylation
Disease Models, Animal
Forkhead Transcription Factors
Graft vs Host Disease
Heterografts
Interferon-gamma
Leukemia
Lymphocyte Activation
Mice
Mice, Knockout
Recurrence
T-Lymphocytes, Regulatory