title: AMP kinase promotes Bcl6 expression in both mouse and human T cells.
abstract: The transcription factor Bcl6 is a master regulator of follicular helper T (TFH) cells, and understanding the signaling pathway that induces Bcl6 and TFHcell differentiation is therefore critical. IL-2 produced during T cell activation inhibits Bcl6 expression but how TFHcells evade IL-2 inhibition is not completely understood. Here we show that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation (GD), and this pathway is insensitive to inhibition by IL-2. Similar to GD, the glucose analog 2-deoxyglucose (2DG) inhibits glycolysis, and 2DG induced Bcl6 expression in activated CD4 T cells. The metabolic sensor AMP kinase (AMPK) is activated when glycolysis is decreased, and the induction of Bcl6 by GD was inhibited by the AMPK antagonist compound C. Additionally, activation of AMPK by the drug AICAR caused Bcl6 up-regulation in activated CD4 T cells. When mice were immunized with KLH using AICAR as an adjuvant, there was a strong TFH-dependent enhancement of KLH-specific antibody (Ab) responses, and higher Bcl6 expression in TFHcells in vivo. Activation of AMPK strongly induced BCL6 and the up-regulation of TFHcell marker expression by human CD4 T cells. Our data reveal a major new pathway for TFHcell differentiation, conserved by both mouse and human T cells. Mature TFHcells are reported to have a lower metabolic state compared to TH1 cells. Our data indicates that decreased metabolism may be deterministic for TFHcell differentiation, and not simply a result of TFHcell differentiation.
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Xie
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Tohti
authors.initials: T
authors.lastname: Amet
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Qigui
authors.initials: Q
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: adent2@iupui.edu.
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Dent
mesh_terms: D000263:Adenylate Kinase / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000096:biosynthesis* / Q000276:immunology; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D051560:Proto-Oncogene Proteins c-bcl-6; D000263:Adenylate Kinase
keywords: AMPK; Bcl6; Metabolism; T follicular helper cells