A molecular mechanism for TNF-α-mediated downregulation of B cell responses

Daniela Frasca, Maria Romero, Alain Diaz, Sarah Alter-Wolf, Michelle Ratliff, Ana Marie Landin, Richard L. Riley, Bonnie B. Blomberg

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

B cell function with age is decreased in class switch recombination (CSR), activation-induced cytidine deaminase (AID), and stability of E47 mRNA. The latter is regulated, at least in part, by tristetraprolin (TTP), which is increased in aged B cells and also negatively regulates TNF-α. In this study, we investigated whether B cells produce TNF-α, whether this changes with age, and how this affects their function upon stimulation. Our hypothesis is that in aging there is a feedback mechanism of autocrine inflammatory cytokines (TNF-α) that lowers the expression of AID and CSR. Our results showed that unstimulated B cells from old BALB/c mice make significantly more TNF-α mRNA and protein than do B cells from young mice, but after stimulation the old make less than the young; thus, they are refractory to stimulation. The increase in TNF-α made by old B cells is primarily due to follicular, but not minor, subsets of B cells. Incubation of B cells with TNF-α before LPS stimulation decreased both young and old B cell responses. Importantly, B cell function was restored by adding anti-TNF-α Ab to cultured B cells. To address a molecular mechanism, we found that incubation of B cells with TNF-α before LPS stimulation induced TTP, a physiological regulator of mRNA stability of the transcription factor E47, which is crucial for CSR. Finally, anti-TNF-α given in vivo increased B cell function in old, but not in young, follicular B cells. These results suggest new molecular mechanisms that contribute to reduced Ab responses in aging.

Original languageEnglish (US)
Pages (from-to)279-286
Number of pages8
JournalJournal of Immunology
Volume188
Issue number1
DOIs
StatePublished - Jan 1 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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