Notch controls the survival of memory CD4+ T cells by regulating glucose uptake


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.

Figure 1: Loss of activated and memory T cells in CD4-specific Notch (Rbpj)-deficient mice.
Figure 2: Notch signaling controls the persistence of pathological autoimmune memory CD4+ T cells.
Figure 3: Dll1 on CD11c+ cells promotes memory CD4+ T cell survival in the bone marrow.
Figure 4: Stat5 and mTOR are not required for maintenance of memory CD4+ T cells in the absence of Notch signaling.
Figure 5: Glucose uptake in memory CD4+ T cells is controlled by Notch signaling.
Figure 6: Notch signaling regulates Glut1 expression in CD4+ T cells via AKT phosphorylation.


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We thank S. Chiba (University of Tsukuba), K. Tanigaki (Shiga Medical Center Research Institute), T. Honjo (Kyoto University), M. Kubo (Tokyo University of Science), M. Farrar (University of Minnesota) and Y. Itoh (Shiga Medical University) for providing mice; T. Azuma (Tokyo Science University) for antibodies; and C. Kinouchi and C. Tomari for technical and editorial assistance. This work was supported by a Grant-in-Aid for Young Scientists (S) from the Japan Society for the Promotion of Science and by a Grant-in-Aid for Scientific Research on Innovative Areas ('Dying Codes') from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.

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Y.M. conducted all of the experiments, analyzed data and wrote the manuscript; C.I. and S.T. contributed to the in vivo T cell transfer studies; K.H. established the Dll1-deficient mouse; H.Y. prepared anti-Dll1 and Dll4 antibodies; and K.Y. supervised the project, analyzed data and wrote the manuscript.

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Correspondence to Koji Yasutomo.

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The authors declare no competing financial interests.

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Maekawa, Y., Ishifune, C., Tsukumo, Si. et al. Notch controls the survival of memory CD4+ T cells by regulating glucose uptake. Nat Med 21, 55–61 (2015).

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