Induction of antigen-specific regulatory T cells following overexpression of a Notch ligand by human B lymphocytes

Stéphane Vigouroux, Eric Yvon, Hans Joachim Wagner, Ettore Biagi, Gianpietro Dotti, Uluhan Sili, Cecilia Lira, Cliona M. Rooney, Malcolm K. Brenner

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

In mice, activation of the Notch pathway in T cells by antigen-presenting cells overexpressing Notch ligands favors differentiation of regulatory T lymphocytes responsible for antigen-specific tolerance. To determine whether this mechanism operates in human T cells, we used Epstein-Barr virus-positive lymphoblastoid cell lines (EBV-LCL) as our (viral) antigen-presenting cells and overexpressed the Notch ligand Jagged-1 (EBV-LCL J1) by adenoviral transduction. The EBV-LCL J1s were cocultured with autologous T cells, and the proliferative and cytotoxic responses to EBV antigens were measured. Transduction had no effect on EBV-LCL expression of major histocompatibility complex (MHC) antigens or of costimulatory molecules CD80, CD86, and CD40. However, we observed a 35% inhibition of proliferation and a >65% reduction in cytotoxic-T-cell activity, and interleukin 10 production was increased ninefold. These EBV-LCL J1-stimulated T lymphocytes act as antigen-specific regulatory cells, since their addition to fresh autologous T cells cultured with autologous nontransduced EBV-LCL cells significantly inhibited both proliferation and cytotoxic effector function. Within the inhibitory population, CD4 +CD25+ and CD8+CD25- T cells had the greatest activity. This inhibition appears to be antigen-specific, since responses to Candida and cytomegalovirus antigens were unaffected. Hence, transgenic expression of Jagged-1 by antigen-presenting cells can induce antigen-specific-regulatory T cells in humans and modify immune responses to viral antigens.

Original languageEnglish (US)
Pages (from-to)10872-10880
Number of pages9
JournalJournal of virology
Volume77
Issue number20
DOIs
StatePublished - Oct 2003

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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