Signal inhibition by the dual-specific phosphatase 4 impairs T cell-dependent B-cell responses with age

• Type of Material: Article
• Authors: Mingcan Yu, Emory University; Guangjin Li, Stanford University; Won-Woo Lee, Seoul National University; Ming Yuan, Georgia Institute of Technology; Dapeng Cui, Emory University; Cornelia M. Weyand, Stanford University; Jorg J. Goronzy, Stanford University
• Language: English
• Date: 2012-04-10
• Publisher: United States National Academy of Sciences
• Publication Version: Final Published Version
• Copyright Statement: © 2012 National Academy of Sciences.
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1109797109
• Title of Journal or Parent Work: PNAS
• Volume: 109
• Issue: 15
• Start Page: E879
• End Page: E888
• Grant/Funding Information: This work was supported by a grant from the Georgia Cancer Coalition and National Science Foundation Grant DMS0847234 Faculty Early Career Development Award (CAREER) (to M. Yuan); National Institutes of Health Grants R01 AR042527 (to C.M.W.), R01 EY011916 (to C.M.W.), R01 AI044142 (to C.M.W.), P01 HL058000 (to C.M.W.), R01 AG015043 (to J.J.G.), U19 AI057266 (to J.J.G.), and U19 AI090019 (to J.J.G.).
• Keywords: Mice; Biomarkers; Adolescent; Dual-Specificity Phosphatases; Gene Silencing; Aged; Immunity, Humoral; Young Adult; Adult; Lymphocyte Activation; Mitogen-Activated Protein Kinase Phosphatases; Aged, 80 and over; Immunologic Memory; Vaccination; Influenza, Human; Animals; B-Lymphocytes; CD4-Positive T-Lymphocytes; Humans; T-Lymphocytes, Helper-Inducer; Aging; Protein Tyrosine Phosphatases; Signal Transduction
• Research Categories: Biology, Microbiology; Health Sciences, Immunology; Health Sciences, Human Development; Engineering, System Science

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.