International Immunology, Vol. 30, No. 6, p. 229 Published by Oxford University Press on behalf of doi:10.1093/intimm/dxy024 The Japanese Society for Immunology 2018. Advance Access publication 9 April 2018 The article ‘Generation of allo-antigen-specific induced Treg To generate allo-antigen-specific iTregs, Kasahara et al. stabilized by vitamin C treatment and its application for preven- culture naive T cells with allogeneic dendritic cells, TGF-β and tion of acute graft versus host disease model’ (doi: 10.1093/ retinoic acid, with or without various pharmacological agents intimm/dxx060), by Hidenori Kasahara et al., has been given the or overexpression of transcription factors. They find that vita- Outstanding Merit Award for 2017; that is, it has been selected min C stabilizes iTreg Foxp3 expression in mice and humans. by the Editor-in-Chief as the best paper published last year in the Especially in humans, vitamin C induces Foxp3-high ‘genu- journal. The full text of the article is available for free online (https:// ine’ iTregs under iTreg conditions (see figure). In a model of doi.org/10.1093/intimm/dxx060) but it is summarized here. acute GVHD, adoptive transfer of such iTregs reduces epi- Down-regulating immune responses is an essential fac- thelial cell death and inflammation in the colon and increases tor in maintaining homeostasis and in preventing diseases the survival of the hosts. Vitamin C actively demethylates such as autoimmunity and allergy; however, it can perpetuate CNS2 in allo-antigen-specific iTregs. The authors discuss the the growth of cancer cells, increase rejection of transplants mechanisms whereby iTregs regulate GVHD, which remain to and allow the development of graft-versus-host disease be clarified. (GVHD). In GVHD, donor cells can directly recognize host Using vitamin C, therefore, increases the stability of Foxp3 allo- antigens. GVHD is still a significant cause of morbidity expression and enhances iTreg-mediated allo-antigen-spe- and mortality after allogeneic transplantation, especially for cific protection from GVHD after transfer following in vitro stem cell transplants. generation. This improves the immunotherapeutic potential Various negative regulatory mechanisms exist in the of Tregs in preventing GVHD and perhaps other unwanted immune system, for example suppressive cytokines, inhibi- immune responses such as autoimmune diseases in tory signaling, T-cell deletion and T-cell anergy. The functional humans. phenomenon of T-cell-mediated immune suppression was established in the 1970s but identifying the so-called ‘sup- pressor T cells’ proved difficult. In the 1980s, recognition of + + + a population of CD4 CD25 Foxp3 regulatory T cells (Tregs) proved to be a paradigm shift, because these cells have suppressor activities. Tregs can be derived from the thymus (tTregs) or be induced outside the thymus (iTregs), in the per- iphery or in vitro. Immunotherapy using Tregs is an attractive approach to reduce GVHD and to combat other diseases. However, although tTregs, for example those isolated from umbilical cords, are stable and effective, it is difficult to prepare large numbers. In contrast, iTregs can be generated in relatively large numbers but they are phenotypically and functionally unstable and can even revert to pathogenic ‘ex-Foxp3’ Tregs. Foxp3 is essential for Treg differentiation, maintenance and function. Treg stability is associated with demethylation at the CNS2 enhancer of the Foxp3 locus whereas iTregs are unstable because of methylation of CNS2. Downloaded from https://academic.oup.com/intimm/article-abstract/30/6/229/4965154 by Ed 'DeepDyve' Gillespie user on 20 June 2018
International Immunology – Oxford University Press
Published: Apr 9, 2018
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