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Diabetes 53:971-977, 2004
© 2004 by the American Diabetes Association, Inc.

Differential Recognition and Activation Thresholds in Human Autoreactive GAD-Specific T-Cells

Roberto Mallone1, Sharon A. Kochik1, Elsa M. Laughlin1, Vivian H. Gersuk1, Helena Reijonen1, William W. Kwok1, and Gerald T. Nepom1,2

1 Benaroya Research Institute at Virginia Mason, Seattle, Washington
2 Department of Immunology, University of Washington School of Medicine, Seattle, Washington

The activation requirements of autoreactive CD4+ T-cells were investigated in GAD65-specific HLA-DR0401–restricted clones derived from a diabetic patient using major histocompatibility complex (MHC) class II tetramers (TMrs) as stimulating agents. Despite the fact that TMrs loaded with an immunodominant-altered GAD peptide (TMr-GAD) bound a limited number of T-cell receptors, they were capable of efficiently delivering activation signals. These signals ranged from the early steps of phospholipase C (PLC)-{gamma}1 phosphorylation and Ca2+ mobilization to more complex events, such as CD69 upregulation, cytokine mRNA transcription and secretion, and proliferation. All the effects triggered by TMr-GAD were dose dependent. On the contrary, [3H]-thymidine incorporation decreased at high TMr-GAD concentrations because of activation-induced cell death (AICD) after initial proliferation. Lower-avidity clones (as defined by TMr-GAD binding) were less sensitive to activation as well as less susceptible to AICD compared with higher-avidity clones. Induction of apoptosis is a potential immunomodulatory target for therapeutic applications of MHC class II multimers, but the relative resistance of low-avidity T-cells may limit its benefits.

Address correspondence and reprint requests to Gerald T. Nepom, MD, PhD, Benaroya Research Institute at Virginia Mason, 1201 Ninth Ave., Seattle, WA 98101-2795. E-mail: nepom{at}benaroyaresearch.org


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