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

Mingcan Yu, Guangjin Li, Won Woo Lee, Ming Yuan, Dapeng Cui, Cornelia M. Weyand, Jor̈g J. Goronzy

Research output: Contribution to journalArticlepeer-review

62 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E879-E888
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number15
DOIs
StatePublished - Apr 10 2012

Keywords

  • Aging
  • Immunosenescence
  • Signaling

ASJC Scopus subject areas

  • General

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