title: Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age.
abstract: T cell-dependent B-cell responses decline with age, suggesting defective CD4 T-cell function. CD4 memory T cells from individuals older than 65 y displayed increased and sustained transcription of the dual-specific phosphatase 4 (DUSP4) that shortened expression of CD40-ligand (CD40L) and inducible T-cell costimulator (ICOS) (both P < 0.001) and decreased production of IL-4, IL-17A, and IL-21 (all P < 0.001) after in vitro activation. In vivo after influenza vaccination, activated CD4 T cells from elderly individuals had increased DUSP4 transcription (P = 0.002), which inversely correlated with the expression of CD40L (r = 0.65, P = 0.002), ICOS (r = 0.57, P = 0.008), and IL-4 (r = 0.66, P = 0.001). In CD4 KO mice reconstituted with DUSP4 OT-II T cells, DUSP4 had a negative effect on the expansion of antigen-specific B cells (P = 0.003) and the production of ova-specific antibodies (P = 0.03) after immunization. Silencing of DUSP4 in memory CD4 T cells improved CD40L (P < 0.001), IL-4 (P = 0.007), and IL-21 (P = 0.04) expression significantly more in the elderly than young adults. Consequently, the ability of CD4 memory T cells to support B-cell differentiation that was impaired in the elderly (P = 0.004) was restored. Our data suggest that increased DUSP4 expression in activated T cells in the elderly in part accounts for defective adaptive immune responses.
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Mingcan
authors.initials: M
authors.lastname: Yu
authors.forename: Guangjin
authors.initials: G
authors.lastname: Li
authors.forename: Won-Woo
authors.initials: WW
authors.lastname: Lee
authors.forename: Ming
authors.initials: M
authors.lastname: Yuan
authors.forename: Dapeng
authors.initials: D
authors.lastname: Cui
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015415:Biomarkers; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D054637:Dual-Specificity Phosphatases / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D007251:Influenza, Human / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014611:Vaccination; D055815:Young Adult
chemical_list: D015415:Biomarkers; D054639:Mitogen-Activated Protein Kinase Phosphatases; C490583:DUSP4 protein, human; D054637:Dual-Specificity Phosphatases; C522186:Dusp4 protein, mouse; D017027:Protein Tyrosine Phosphatases