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Restricted Autoantigen Recognition Associated with Deletional and Adaptive Regulatory Mechanisms¹

John A. Gebe^2,*, Betty B. Yue^*, Kelly A. Unrath, Ben A. Falk^* and Gerald T. Nepom^*,

^* Benaroya Research Institute, Seattle WA 98101; Department of Botany and Plant Pathology, Oregon State University, Corvallis, OR 97331; and Department of Immunology, University of Washington School of Medicine, Seattle WA 98195

Autoimmune diabetes (T1D) is characterized by CD4⁺ T cell reactivity to a variety of islet-associated Ags. At-risk individuals, genetically predisposed to T1D, often have similar T cell reactivity, but nevertheless fail to progress to clinically overt disease. To study the immune tolerance and regulatory environment permissive for such autoreactive T cells, we expressed TCR transgenes derived from two autoreactive human T cells, 4.13 and 164, in HLA-DR4 transgenic mice on a C57BL/6-derived "diabetes-resistant" background. Both TCR are responsive to an immunodominant epitope of glutamic acid decarboxylase 65_555–567, which is identical in sequence between humans and mice, is restricted by HLA-DR4, and is a naturally processed self Ag associated with T1D. Although both TCR use the identical V and Vβ genes, differing only in CDR3, we found stark differences in the mechanisms utilized in vivo in the maintenance of immune tolerance. A combination of thymic deletion (negative selection), TCR down-regulation, and peripheral activation-induced cell death dominated the phenotype of 164 T cells, which nevertheless still maintain their Ag responsiveness in the periphery. In contrast, 4.13 T cells are much less influenced by central and deletional tolerance mechanisms, and instead display a peripheral immune deviation including differentiation into IL-10-secreting Tr1 cells. These findings indicate a distinct set of regulatory alternatives for autoreactive T cells, even within a single highly restricted HLA-peptide-TCR recognition profile.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by National Institutes of Health Grant AI050864 and United States Army Medical Research Acquisition Activity Grant PR064261.

² Address correspondence and reprint requests to Dr. John A. Gebe, Department of Diabetes, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101. E-mail address: jgebe{at}benaroyaresearch.org

³ Abbreviations used in this paper: Treg, regulatory T cell; GAD, glutamic acid decarboxylase; T1D, type 1 diabetes.

⁴ The online version of this article contains supplemental material.