title: Notch controls the survival of memory CD4+ T cells by regulating glucose uptake.
abstract: CD4+ T cells differentiate into memory T cells that protect the host from subsequent infection. In contrast, autoreactive memory CD4+ T cells harm the body by persisting in the tissues. The underlying pathways controlling the maintenance of memory CD4+ T cells remain undefined. We show here that memory CD4+ T cell survival is impaired in the absence of the Notch signaling protein known as recombination signal binding protein for immunoglobulin κ J region (Rbpj). Treatment of mice with a Notch inhibitor reduced memory CD4+ T cell numbers and prevented the recurrent induction of experimental autoimmune encephalomyelitis. Rbpj-deficient CD4+ memory T cells exhibit reduced glucose uptake due to impaired AKT phosphorylation, resulting in low Glut1 expression. Treating mice with pyruvic acid, which bypasses glucose uptake and supplies the metabolite downstream of glucose uptake, inhibited the decrease of autoimmune memory CD4+ T cells in the absence of Notch signaling, suggesting memory CD4+ T cell survival relies on glucose metabolism. Together, these data define a central role for Notch signaling in maintaining memory CD4+ T cells through the regulation of glucose uptake.
authors.affiliation: Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Maekawa
authors.affiliation: Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.
authors.forename: Chieko
authors.initials: C
authors.lastname: Ishifune
authors.affiliation: Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukumo
authors.affiliation: Department of Immunology and Research Center for Embryogenesis and Organogenesis, Tokai University School of Medicine, Kanagawa, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yasutomo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005947:Glucose / Q000276:immunology / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000172:deficiency / Q000235:genetics; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D051272:Glucose Transporter Type 1; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497571:Rbpj protein, mouse; D011948:Receptors, Antigen, T-Cell; D051880:Receptors, Notch; C495678:Slc2a1 protein, mouse; D051058:Oncogene Protein v-akt; D005947:Glucose