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Loss of Invariant Chain Protects Nonobese Diabetic Mice against Type 1 Diabetes¹

Richard J. Mellanby^*, Chad H. Koonce, Anthony Monti, Jenny M. Phillips^*, Anne Cooke^2,* and Elizabeth K. Bikoff^2,3,

^* Department of Pathology, University of Cambridge, Cambridge, United Kingdom; and Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom.

The invariant (Ii) chain acts as an essential chaperone to promote MHC class II surface expression, Ag presentation, and selection of CD4⁺ T cells. We have examined its role in the development of type 1 diabetes in NOD mice and show that Ii chain-deficient NOD mice fail to develop type 1 diabetes. Surprisingly, Ii chain functional loss fails to disrupt in vitro presentation of islet Ags, in the context of NOD I-A^g7 molecules. Moreover, pathogenic effector cells could be shown to be present in Ii chain-deficient NOD mice because they were able to transfer diabetes to NOD.scid recipients. The ability of these cells to transfer diabetes was markedly enhanced by depletion of CD25 cells coupled with in vivo anti-CD25 treatment of recipient mice. The numbers of CD4⁺CD25⁺Foxp3⁺ T cells in thymus and periphery of Ii chain-deficient NOD mice were similar to those found in normal NOD mice, in contrast to conventional CD4⁺ T cells whose numbers were reduced. This suggests that regulatory T cells are unaffected in their selection and survival by the absence of Ii chain and that an alteration in the balance of effector to regulatory T cells contributes to diabetes prevention.

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 the Wellcome Trust.

² A.C. and E.K.B. are joint senior authors.

³ Address correspondence and reprint requests to Dr. Elizabeth K. Bikoff, Wellcome Trust Center for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom. E-mail address: elizabeth.bikoff{at}well.ox.ac.uk

⁴ Abbreviations used in this paper: Treg, regulatory T cell; ER, endoplasmic reticulum; cat, cathepsin; Ii, invariant; PLN, pancreatic draining lymph node; MLN, mesenteric lymph nodes.