The Journal of Experimental Medicine
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Published online 6 June 1999.
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© The Rockefeller University Press, 0022-1007/2000/6/2021/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 11, June 5, 2000 2021-2028

BDR

Role of Antigen-presenting Cells in Mediating Tolerance and Autoimmunity

Kristine M. Garzaa, Steven M. Chana, Rakesh Suria, Linh T. Nguyena, Bernhard Odermattb, Stephen P. Schoenbergerc, and Pamela S. Ohashia
a Departments of Medical Biophysics and Immunology, Ontario Cancer Institute, Toronto, Ontario M5G 2M9, Canada
b Institute of Pathology, Department of Experimental Pathology, University Hospital, 8091 Zurich, Switzerland
c Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, California 92121

Correspondence to: Pamela S. Ohashi, Ontario Cancer Institute, 610 University Ave., Toronto, ON M5G 2M9, Canada. Tel:416-946-2000 Fax:416-946-2086 E-mail:pohashi{at}oci.utoronto.ca.

The mechanisms that determine whether receptor stimulation leads to lymphocyte tolerance versus activation remain poorly understood. We have used rat insulin promoter (RIP)-gp/P14 double-transgenic mice expressing the lymphocytic choriomeningitis virus (LCMV) glycoprotein (gp) on pancreatic ß-islet cells together with T cells expressing an LCMV-gp–specific T cell receptor to assess the requirements for the induction of autoimmunity. Our studies have shown that administration of the gp peptide gp33 leads to the activation of P14-transgenic T cells, as measured by the upregulation of activation markers and the induction of effector cytotoxic activity. This treatment also leads to expansion and deletion of P14 T cells. Despite the induction of cytotoxic T lymphocyte activity, peptide administration is not sufficient to induce diabetes. However, the administration of gp peptide together with an activating anti-CD40 antibody rapidly induces diabetes. These findings suggest that the induction of tolerance versus autoimmunity is determined by resting versus activated antigen-presenting cells.

Key Words: activation, CTL, diabetes, CD40, costimulation


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