Plasticity of human gamma/delta T cells: Modulation by Vitamin C

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During the first funding period of 24 months, we demonstrated that Vitamin C (VitC) increases significantly the activation and effector functions of human gamma/delta T cells. VitC increases the proliferative activity, the metabolic activity, and the cytokine production in gamma/delta T cells. However, we also showed that VitC, in the additional presence of transforming growth factor-beta (TGF-beta), upregulates the expression of the transcription factor FOXP3 and induces suppressive activity in human gamma/delta T cells, associated with strong hypomethylation in specific regions of the FOXP3 gene. Transcriptome analysis performed by RNAseq and genome-wide methylation studies identified several candidates of VitC-regulated genes in human gamma/delta T cells. We also contributed to a clinical phase I study where allogeneic gamma/delta T cells expanded in presence of VitC were adoptively transferred into cancer patients. The results of the first funding period have been published in three original papers. Based on these results, the goal of the present renewal proposal is to investigate further the influence of VitC on the plasticity of human gamma/delta T cells. We will focus on the following research questions: (1) How does VC modulate T-cell receptor signaling in gamma/delta T cells and what is the significance of some of the VitC-regulated genes identified in our previous studies; (2) how does VitC increase the cytotoxic effector function of gamma/delta T cells? (3) How does VitC in combination with other, clinically relevant epigenetic modifiers such as histone deacetylase inhibitors modulate the activation and effector functions of human gamma/delta T cells? The overall goal of this project is to optimize the effector function of human gamma/delta T cells for application in cellular immunotherapy.