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      Connections Between Metabolism and Epigenetics in Programming Cellular Differentiation

      1 , 1
      Annual Review of Immunology
      Annual Reviews

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          Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade.

          Blocking Programmed Death-1 (PD-1) can reinvigorate exhausted CD8 T cells (TEX) and improve control of chronic infections and cancer. However, whether blocking PD-1 can reprogram TEX into durable memory T cells (TMEM) is unclear. We found that reinvigoration of TEX in mice by PD-L1 blockade caused minimal memory development. After blockade, reinvigorated TEX became reexhausted if antigen concentration remained high and failed to become TMEM upon antigen clearance. TEX acquired an epigenetic profile distinct from that of effector T cells (TEFF) and TMEM cells that was minimally remodeled after PD-L1 blockade. This finding suggests that TEX are a distinct lineage of CD8 T cells. Nevertheless, PD-1 pathway blockade resulted in transcriptional rewiring and reengagement of effector circuitry in the TEX epigenetic landscape. These data indicate that epigenetic fate inflexibility may limit current immunotherapies.
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            T cell metabolism drives immunity

            Buck et al. discuss the role of lymphocyte metabolism on immune cell development and function.
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              A critical role for Dnmt1 and DNA methylation in T cell development, function, and survival.

              The role of DNA methylation and of the maintenance DNA methyltransferase Dnmt1 in the epigenetic regulation of developmental stage- and cell lineage-specific gene expression in vivo is uncertain. This is addressed here through the generation of mice in which Dnmt1 was inactivated by Cre/loxP-mediated deletion at sequential stages of T cell development. Deletion of Dnmt1 in early double-negative thymocytes led to impaired survival of TCRalphabeta(+) cells and the generation of atypical CD8(+)TCRgammadelta(+) cells. Deletion of Dnmt1 in double-positive thymocytes impaired activation-induced proliferation but differentially enhanced cytokine mRNA expression by naive peripheral T cells. We conclude that Dnmt1 and DNA methylation are required for the proper expression of certain genes that define fate and determine function in T cells.
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                Author and article information

                Journal
                Annual Review of Immunology
                Annu. Rev. Immunol.
                Annual Reviews
                0732-0582
                1545-3278
                April 26 2018
                April 26 2018
                : 36
                : 1
                : 221-246
                Affiliations
                [1 ]Department of Microbiology, University of Alabama at Birmingham, Alabama 35294, USA;,
                Article
                10.1146/annurev-immunol-042617-053127
                29328786
                19fa9193-d456-4274-a245-bfc1371db21b
                © 2018
                History

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