H2E-derived Eα52-68 peptide presented by H2A^b interferes with clonal deletion of autoreactive T cells in autoimmune thyroiditis

Susceptibility and resistance to experimental autoimmune thyroiditis is encoded by MHC H2A genes. We reported that traditionally resistant BIO (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 Eb expression on mTg presentation by A ^b, seven putative A^b-binding, 15-16-mer peptides were synthesized. Five were immunogenic for both BIO and E⁺B10 mice. The effect of E^b expression was tested by competition with an Eα52-68 peptide, because Eα52-68 occupies ∼15% of A^b molecules in E⁺B10 mice, binding with high affinity. Eα52-68 competitively reduced the proliferative response to mTg, mTgl677, and mTg2342 of lymph node cells primed to each Ag. Moreover, mTgl677 induced mild thyroiditis in Treg-depleted BIO mice, and in E⁺B10 mice without the need for Treg depletion. Eα52-68 competition with mTg-derived peptides may impede clonal deletion of pathogenic, mTg-specific T cells in the thymus.