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H2E-Derived E52-68 Peptide Presented by H2A^b Interferes with Clonal Deletion of Autoreactive T Cells in Autoimmune Thyroiditis¹

Nicholas K. Brown^*, Daniel J. McCormick, Chella S. David and Yi-chi M. Kong^2,*

^* Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201; and Department of Biochemistry and Molecular Biology and Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905

Susceptibility and resistance to experimental autoimmune thyroiditis is encoded by MHC H2A genes. We reported that traditionally resistant B10 (H2^b) mice permit thyroiditis induction with mouse thyroglobulin (mTg) after depleting regulatory T cells (Tregs), supporting A^b presentation to thyroiditogenic T cells. Yet, Ea^k transgenic mice, expressing A^b and normally absent E^b molecules (E⁺B10 mice), are susceptible to thyroiditis induction without Treg depletion. To explore the effect of E^b expression on mTg presentation by A^b, seven putative A^b-binding, 15–16-mer peptides were synthesized. Five were immunogenic for both B10 and E⁺B10 mice. The effect of E^b expression was tested by competition with an E52-68 peptide, because E52-68 occupies 15% of A^b molecules in E⁺B10 mice, binding with high affinity. E52-68 competitively reduced the proliferative response to mTg, mTg1677, and mTg2342 of lymph node cells primed to each Ag. Moreover, mTg1677 induced mild thyroiditis in Treg-depleted B10 mice, and in E⁺B10 mice without the need for Treg depletion. E52-68 competition with mTg-derived peptides may impede clonal deletion of pathogenic, mTg-specific T cells in the thymus.

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 National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases Grant 45960 (to Y.M.K.).

² Address correspondence and reprint requests to Dr. Yi-chi M. Kong, Department of Immunology and Microbiology, Wayne State University School of Medicine, 540 East Canfield Avenue, Detroit, MI 48201. E-mail address: ykong{at}med.wayne.edu

³ Abbreviations used in this paper: EAT, experimental autoimmune thyroiditis; mTg, mouse thyroglobulin; h, human; Treg, regulatory T cell; SC, spleen cell; LNC, lymph node cell; SI, stimulation index; CIA, collagen-induced arthritis; NMS, normal mouse serum.