Suppressive effects of vitamin C-treated induced-regulatory T cells on heart allograft rejection under vitamin C-deficient or –sufficient conditions

Abstract

Foxp3 stability of vitamin C-treated induced-regulatory T cells (V-iTregs) is superior to that of conventional iTregs (C-iTregs). However, the role of V-iTregs in allograft rejection under vitamin C-deficient conditions, such as those seen in humans, remains unclear. We aimed to elucidate the role of vitamin C treatment on generation and maintenance of iTregs from gulo knockout (Gulo-KO) mice as well as wild type (WT) mice, and in vitro and in vivo suppressive effects of V-iTregs on heart allograft rejection in either Gulo-KO or WT recipient mice. Conversion efficiency of iTregs was similar between C- and V-iTregs in both WT and Gulo-KO mice. V-iTregs from WT or Gulo-KO mice showed better in vitro Foxp3 stability than C-iTregs, although there was no difference between WT V-iTregs and Gulo-KO V-iTregs. Furthermore, V-iTregs from WT or Gulo-KO mice suppressed in vitro T cell proliferation better than C-iTregs. Heterotrophic heart transplantation from BALB/c mice to WT or vitamin C-deficient Gulo-KO C57BL/6J mice was performed following adoptive transfer of C- or V-iTregs. V-iTregs as well as C-iTregs prolonged heart allograft survival in WT and Gulo-KO mice. However, there was no difference between the C- and V-iTreg groups. Supplementation of low- or high-dose vitamin C did not induce significant changes in heart allograft survival in Gulo-KO recipients that had received V-iTregs. In conclusion, V-iTregs do not exert better suppressive effects on heart allograft survival than C-iTregs in either WT or vitamin C-deficient recipients.

Vitamin C Differentially Impacts the Serum Proteome Profile in Female and Male Mice

“…Clinically relevant animal models of vitamin C (ascorbate) synthesis deficiency are essential for improving our understanding of the role of ascorbate in the pathogenesis of complex diseases . In this context, the Gulo –/– mouse is a relevant model to examine the impact of ascorbate on different biological processes in vivo . − Importantly, the levels of ascorbate found in the serum of Gulo –/– mice will reflect the amounts of ascorbate provided in drinking water. Moreover, it was found that serum ascorbate concentrations showed a sigmoid-shaped dose–response curve similar to that observed in human studies. , By simply changing the amount of ascorbate in drinking water, we can control the concentration of ascorbate in the serum of these mice in a noninvasive manner and study its impact on different biological processes in vivo .…”

Understanding Vitamin C: Comprehensive Examination of Its Biological Significance and Antioxidant Properties

“…Understanding Vitamin C: Comprehensive Examination of Its Biological Significance… DOI: http://dx.doi.org/10.5772/intechopen.114122 including mice, are capable of synthesizing vitamin C from glucose, while humans and other primates meet their daily requirements for it through their diet because they lack the L-gulono-g-lactone oxidase enzyme involved in vitamin C synthesis [14][15][16].…”

Micro but mighty—Micronutrients in the epigenetic regulation of adaptive immune responses*

“…95,96 In an allogeneic heart transplant model, however, iTreg cells differentiated in the presence or absence of VC similarly promoted the survival of heart allografts. 97 Therefore, the effect of VC on epigenome remodeling warrants further investigation to improve adoptive immune cell therapy, especially for specific immunosuppression.…”