H2A- and H2E-derived CD4⁺CD2⁺ regulatory T cells: A potential role in reciprocal inhibition by class II genes in autoimmune thyroiditis

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.