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H2A- and H2E-Derived CD4⁺CD25⁺ Regulatory T Cells: A Potential Role in Reciprocal Inhibition by Class II Genes in Autoimmune Thyroiditis¹

Gerald P. Morris^*, Yan Yan^*, 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 Immunology, Mayo Clinic, Rochester, MN 55905

We recently described a novel H2E class II-transgenic model (A^–E⁺) of experimental autoimmune thyroiditis (EAT) that permits disease induction with heterologous thyroglobulin (Tg), but unlike conventional susceptible strains, precludes self-reactivity to autologous mouse Tg. In transgenic E⁺B10 (A⁺E⁺) mice, the presence of endogenous H2A genes is protective against H2E-mediated thyroiditis, inhibiting EAT development. The suppressive effect of H2A genes on H2E-mediated thyroiditis mirrors previous reports of H2E suppression on H2A-mediated autoimmune diseases, including EAT. The mechanism of the reciprocal-suppressive effect between class II genes is unclear, although the involvement of regulatory T cells has been proposed. We have recently reported that CD4⁺CD25⁺ regulatory T cells mediate peripheral tolerance induced with mouse Tg in CBA mice. To determine whether these cells play a role in our E⁺-transgenic model, we first confirmed the existence of CD4⁺CD25⁺ T cells regulating thyroiditis in E⁺B10.Ab⁰ (A^–E⁺) and B10 (A⁺E^–) mice by i.v. administration of CD25 mAb before EAT induction. The depletion of CD4⁺CD25⁺ T cells enhanced thyroiditis induction in the context of either H2E or H2A. Moreover, reconstitution of CD4⁺CD25⁺ T cells from naive B10 mice restored resistance to EAT. E⁺B10 (A⁺E⁺) mice were also depleted of CD4⁺CD25⁺ T cells before the challenge to determine their role in thyroiditis in the presence of both H2A and H2E genes. Depletion of CD4⁺CD25⁺ regulatory T cells offset the suppression of H2E-mediated thyroiditis by H2A. Thus, these regulatory T cells may be involved in the reciprocal-suppressive effect between class II genes.

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