Editors' ChoiceREGULATORY T CELLS

Scientists flip-flop: Vitamin C suppresses immunity

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Science Translational Medicine  30 Mar 2016:
Vol. 8, Issue 332, pp. 332ec51
DOI: 10.1126/scitranslmed.aaf6466

After decades of debate, immunologists agree that a specific class of T cells naturally functions to suppress immune responses in an antigen-specific manner. Like perfect diamonds, these regulatory T cells (Tregs) are rare, which limits their use as an immunosuppressive agent to treat autoimmune disease and rejection of organ transplants. Although Tregs can be induced from conventional CD4+ T cells in vitro, proliferation in vivo after adoptive transfer of induced Tregs (iTregs) reduces expression of the gene encoding Foxp3, a transcription factor essential for Treg development and function. Methylation at conserved noncoding DNA sequences (CNS) in the Foxp3 gene results in this loss of expression, but the way in which Tregs normally maintain demethylated CNS in vivo was unknown. Now, two groups (Yue et al. and Nair et al.) demonstrate that this DNA demethylation is mediated, in human and mouse Tregs, by the Ten-eleven translocation enzymes (TETs), which oxidize 5-methylcytosine into 5-hydroxymethylcytosine, a precursor to unmethylated cytosine.

Using knockout mice, the groups reveal a redundant but essential role of TETs in maintaining demethylated CNSs in iTregs and for keeping Foxp3 expression stable over cell divisions. Vitamin C has been shown to keep TETs active by reducing Fe3+ to Fe2+ at the enzymes’ active site; this function is similar to vitamin C’s role in reactivating spent prolyl and lysyl hydroxylases, enzymes that are essential for the quaternary structure of collagen and prevention of scurvy. Both groups show that vitamin C (in the form of ascorbic acid) potentiates TET-mediated CNS demethylation and resistance to the loss of Foxp3 expression in iTregs after adoptive transfer into mice. Furthermore, Yue et al. find that the same pathway is active in iTregs induced from sorted human peripheral blood T cells; through potentiation of TETs, vitamin C stabilizes Foxp3 expression and iTreg suppressor function to levels comparable with those in Tregs differentiated in vivo. Moving beyond iTregs, Nair et. al. administered sulfinpyrazone, an inhibitor of a cellular vitamin C transporter, to Foxp3-GFP transgenic reporter mice in a colitis model to show that CNS demethylation and maintenance of in vivo-generated Tregs is also dependent on TETs and vitamin C. Collectively, these studies indicate that vitamin C preserves the immunosuppressive capacity of both in vitro and in vivo-generated Tregs.

Vitamin C is necessary in the human diet, but mice synthesize this nutrient, which has been assigned many roles since the days when Linus Pauling zealously recommended boosting immunity through megadose supplementation to treat the common cold and prevent cancer. The new findings may have you believe that vitamin C does the opposite of enhancing immunity. But wait. Before you question your next bite of an orange, note that vitamin C's benefit on the maintenance of iTregs peaked at 10 µg/mL (~50 µM), which is the average serum level in adults. Thus, it is unlikely that increasing vitamin C levels above normal will increase the suppressive capacity of in vivo Tregs. However, what these findings do tell us is that vitamin C or other molecules that are more selective for TETs might be tools for potentiating and stabilizing in vitro-generated Tregs.

X. Yue et al., Control of Foxp3 stability through modulation of TET activity. J. Exp. Med. 213, 377–397 (2016). [Abstract]

V. S. Nair et al., Vitamin C facilitates demethylation of the Foxp3 enhancer in a Tet-dependent manner. J. Immunol. 196, 2119–2131 (2016). [Abstract]

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