Different development of myelin basic protein agonist- and antagonist-specific human TCR transgenic T cells in the thymus and periphery

Myelin basic protein (MBP)-specific T cells are thought to play a role in the development of multiple sclerosis. MBP residues 111-129 compose an immunodominant epitope cluster restricted by HLA-DRB1*0401. The sequence of residues 111-129 of MBP (MBP_111-129) differs in humans (MBP122:Arg) and mice (MBP122:Lys) at aa 122. We previously found that ∼50% of human MBP_111-129 (MBP122: Arg)-specific T cell clones, including MS2-3C8 can proliferate in response to mouse MBP_111-129 (MBP122:Lys). However, the other half of T cell clones, including HD4-1C2, cannot proliferate in response to MBP111-129 (MBP122:Lys). We found that MBP_111-129 (MBP122: Lys) is an antagonist for HD4-1C2 TCR, therefore, MS2-3C8 and HD4-1C2 TCRs are agonist- and antagonist-specific TCRs in mice, respectively. Therefore, we examined the development of HD4-1C2 TCR and MS2-3C8 TCR transgenic (Tg) T cells in the thymus and periphery. We found that dual TCR expression exclusively facilitates the development of MBP_111-129 TCR Tg T cells in the periphery of HD4-1C2 TCR/HLA-DRB1*0401 Tg mice although it is not required for their development in the thymus. We also found that MS2-3C8 TCR Tg CD8 ⁺ T cells develop along with MS2-3C8 TCR Tg CD4 T cells, and that dual TCR expression was crucial for the development of MS2-3C8 TCR Tg CD4 ⁺ and CD8⁺ T cells in the thymus and periphery, respectively. These results suggest that thymic and peripheral development of MBP-specific T cells are different; however, dual TCR expression can facilitate their development.