A comparative view on vitamin C effects on αβ- versus γδ T-cell activation and differentiation

Abstract

Vitamin C (VitC) is an essential vitamin that needs to be provided through exogenous sources. It is a potent anti-oxidant, and an essential cofactor for many enzymes including a group of enzymes that modulate epigenetic regulation of gene expression. Moreover, VitC has a significant influence on T-cell differentiation, and can directly interfere with T-cell signaling. Conventional CD4 and CD8 T cells express the TCR and recognize peptide antigens in the context of MHC presentation. The numerically small population of T cells recognizes antigens in an MHC-independent manner. T cells kill a broad variety of malignant cells, and because of their unique features, are interesting candidates for cancer immunotherapy. In this review, we summarize what is known about the influence of VitC on T-cell activation and differentiation with a special focus on T cells. The known mechanisms of action of VitC on T cells are discussed and extrapolated to the effects observed on T-cell activation and differentiation. Overall, VitC enhances proliferation and effector functions of T cells and thus may help to increase the efficacy of T cells applied as cancer immunotherapy in adoptive cell transfer.

Cancer immunotherapy with γδ T cells: many paths ahead of us

“…To conclude, the effect of Vit C on γδ T cell plasticity depends on the overall environmental signals. 166 , 167 As discussed above, Vit C actually conveys a regulatory phenotype and induces FOXP3 hypomethylation in the additional presence of TGF-β. 112 However, in the absence of TGF-β during the expansion phase, Vit C substantially enhances effector functions desired in the context of cancer immunotherapy.…”

“…Vitamin C (Vit C, L-ascorbic acid), an essential vitamin, plays an important role in remodeling the epigenome 165 and impacts T cell activation at multiple levels. 166 The mechanistic basis of its action implies an interplay between antioxidant potential and (epi)genetic regulation of gene expression. We have investigated the effects of Vit C and the more stable phospho-modified L-ascorbic acid 2-phosphate (pVC) on the in vitro activation of Vδ2T cells.…”

Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

“…29 Vitamin C is a potent antioxidant and epigenetic modifier that has been shown to modulate T-cell differentiation. 37 However, the development of a new optimal expansion formula for Vγ9Vδ2 T cells resulting in stronger cytotoxicity remains a pressing need.…”

Vitamin C, From Supplement to Treatment: A Re-Emerging Adjunct for Cancer Immunotherapy?

“…This ROSbuffering activity influences cell signal transduction, and the influence of physiologic doses of VitC on TCR signal transduction in general has been recently reviewed. Possible targets include molecules in the proximal TCR signaling complex, as well as downstream signaling molecules such as p38, Erk1/2, NF-kB, NFAT, and PI3K-Akt-mTOR pathway members (43,44).…”

“…Despite their overall structural similarity, there are significant differences in proximal signaling after antigen recognition between CARs and TCRs (83,84). However, given that VitC can modulate activation-induced TCR signaling (43), it is probable that VitC affects proximal CAR signaling. Additionally, gd T cells treated with pVC have reduced ROS levels, and ROS are known to interact with molecules involved in proximal TCR signaling (85).…”