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Journal of Virology, October 2003, p. 10872-10880, Vol. 77, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.20.10872-10880.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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, and Malcolm K. Brenner*

Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas

Received 5 March 2003/ Accepted 22 July 2003

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.

* Corresponding author. Mailing address: Center for Cell and Gene Therapy, Baylor College of Medicine, 6621 Fannin St., Houston, TX 77030. Phone: (832) 824-4663. Fax: (832) 825-4668. E-mail: mkbrenne{at}txccc.org.

Journal of Virology, October 2003, p. 10872-10880, Vol. 77, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.20.10872-10880.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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