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Equivalent Specificity of Peripheral Blood and Islet-Infiltrating CD8⁺ T Lymphocytes in Spontaneously Diabetic HLA-A2 Transgenic NOD Mice¹

Emmanuelle Énée^*, Emanuela Martinuzzi^*, Philippe Blancou, Jean-Marie Bach, Roberto Mallone^* and Peter van Endert^2,*,

^* Institut National de la Santé et de la Recherche Médicale, Unité 580; Université Paris Descartes, Faculté de Médecine René Descartes, Paris; and Immuno-Endocrinology Unité Mixte de Recherche 707, Institut National de la Recherche Agronomique/École Nationale Vétérinaire de Nantes/Université, Nantes, France

CD8⁺ T cells play an important role in the initiation of insulitis and in the destructive stage leading to insulin-dependent diabetes mellitus. A string of recent studies has led to the identification of numerous HLA-A2-restricted epitopes derived from pancreatic β cell Ags. It is hoped that assays detecting responses of patient PBMC to such epitopes might be instrumental for early diagnosis of β cell-directed autoimmunity and for monitoring trials of immunointervention. However, it remains unclear whether the results of assays studying PBMC reflect responses of islet-infiltrating lymphocytes, and to what extent they correlate with disease risk and/or activity. We have used female and male humanized NOD mice expressing HLA-A2 in addition to murine MHC class I molecules to study spontaneous responses of islet-infiltrating blood, spleen, and lymph node lymphocytes of various age groups to a panel of 16 epitopes. Twelve of these are restricted by HLA-A2, have previously been shown to be recognized by patient CTL, and have identical sequences in human and murine autoantigens. Using an IFN- ELISPOT assay, we find highly similar hierarchies of epitope immunodominance in the different T cell compartments, including peripheral blood and pancreatic islets. Moreover, we demonstrate that most of the epitopes eliciting dominant responses in humans display similar status in the mouse model. These results emphasize the potential of humanized mice as tools for studying spontaneous autoimmune CTL responses, and they provide a strong rationale for the development and use of assays monitoring responses of CD8⁺ PBMC in human type 1 diabetes.

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 work was supported by Grant 05-PCOD-036 of the Agence Nationale de Recherche and by a grant from the European Foundation for the Study of Diabetes.

² Address correspondence and reprint requests to Dr. Peter van Endert, Institut National de la Santé et de la Recherche Médicale Unité 580, Hôpital Necker, 161 rue de Sèvres, 75015 Paris, France. E-mail address: vanendert{at}necker.fr

³ Abbreviations used in this paper: IDDM, insulin-dependent diabetes mellitus; PPI, preproinsulin; GAD, glutamic acid decarboxylase; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; SFC, spot-forming cells.