AUTHOR=Fujiki Fumihiro , Morimoto Soyoko , Katsuhara Akiko , Okuda Akane , Ogawa Saeka , Ueda Eriko , Miyazaki Maki , Isotani Ayako , Ikawa Masahito , Nishida Sumiyuki , Nakajima Hiroko , Tsuboi Akihiro , Oka Yoshihiro , Nakata Jun , Hosen Naoki , Kumanogoh Atsushi , Oji Yusuke , Sugiyama Haruo TITLE=T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.935465 DOI=10.3389/fimmu.2022.935465 ISSN=1664-3224 ABSTRACT=

Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.