J. Exp. Med., Volume 187, Number 3, February 2, 1998 427-432

BRIEF DEFINITIVE REPORT:
Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4) Regulates the Unfolding of Autoimmune Diabetes

By Fred Lühder,^* Petter Höglund,^* James P. Allison, Christophe Benoist,^* and Diane Mathis^*

From the ^* Institut de Génétique et de Biologie Moléculaire et Cellulaire (CNRS/INSERM/ULP), 1 rue Laurent Fries, 67404 Illkirch, Communanté Urbain de Strasbourg, France; and the  Howard Hughes Medical Institute, Cancer Research Laboratory, University of California, Berkeley, California 94720-0001

Evidence has been accumulating that shows that insulin-dependent diabetes is subject to immunoregulation. To determine whether cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is involved, we injected anti-CTLA-4 mAb into a TCR transgenic model of diabetes at different stages of disease. When injected into young mice, months before they would normally become diabetic, anti-CTLA-4 induced diabetes rapidly and essentially universally; this was not the result of a global activation of T lymphocytes, but did reflect a much more aggressive T cell infiltrate in the pancreatic islets. These effects were only observed if anti-CTLA-4 was injected during a narrow time window, before the initiation of insulitis. Thus, engagement of CTLA-4 at the time when potentially diabetogenic T cells are first activated is a pivotal event; if engagement is permitted, invasion of the islets occurs, but remains quite innocuous for months, if not, insulitis is much more aggressive, and diabetes quickly ensues.

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