title: Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways.
abstract: The percentage of late/exhausted memory (LM) B cells increases with age and we show here that this is associated with a lower influenza vaccine response. To identify novel contributors to the phenotypic and functional changes observed in aged B cells, we sorted the major peripheral B cell subsets [naïve, IgM memory, switched memory (swIg) and late/exhausted memory (LM)] and determined their percentages in the peripheral blood as well as their level of immune activation by measuring basal levels of expression of multiple senescence-associated secretory phenotype (SASP) markers, such as pro-inflammatory cytokines (TNF-α/IL-6/IL-8), inflammatory micro-RNAs (miRs, miR-155/16/93), cell cycle regulators (p16INK4). We found that only memory B cells express SASP markers, and especially the LM B cell subset, which is also showing spontaneous activation of AMP-activated protein kinase (AMPK), the energy sensing enzyme which is ubiquitously expressed in mammalian cells. LM B cells, but not IgM memory B cells, activate a p38MAPK signaling pathway, downstream of AMPK, leading to the expression of SASP mediators, while class switch recombination is downregulated. These data show that some B cell subsets are more inflammatory than others, that they are pre-activated and that this signaling through metabolic pathways is associated with a senescence phenotype, demonstrating for the first time in human B lymphocytes the link between aging, cellular senescence, SASP and metabolism.
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA. Electronic address: dfrasca@med.miami.edu.
authors.forename: Daniela
authors.initials: D
authors.lastname: Frasca
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Diaz
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Romero
authors.affiliation: Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
authors.forename: Bonnie B
authors.initials: BB
authors.lastname: Blomberg
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D016922:Cellular Senescence; D016207:Cytokines / Q000097:blood*; D005260:Female; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D053858:Metabolic Networks and Pathways; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged
chemical_list: D015415:Biomarkers; D016207:Cytokines; D035683:MicroRNAs; D055372:AMP-Activated Protein Kinases
keywords: Aging; B cells; Inflammation; SASP; Vaccine responses