The role of self-peptides in intrathymic T cell positive selection

The generation of mature alpha beta T cells is directly dependent on molecu lar interactions between the TCR and the MHC interaction during intrathymic development. Pioneering experiments using mice bearing spontaneous MHC cla ss I molecules mutations, which affect peptide binding but not the TCR/MHC interaction, have suggested an important role for self-peptides in the deve lopment of mature CD8(+) T lymphocytes. This idea received considerable sup port when mice deficient for MHC class I molecules were used: fetal thymic organ culture experiments demonstrated that all the peptides able to restor e surface expression of MHC class I molecules do not necessarily restore th e development of CD8(+) thymocytes. Additionally, a mixture of different pe ptides was found to be more efficient than individual peptides in driving p ositive selection, suggesting that self complexity controls optimal T cell positive selection. Recent in vitro observations obtained with genetically modified mice indicate that this notion also applies to the development of CD4(+) thymocytes. For instance, normal expression of MHC class II molecule s, which display a very restricted set of self-peptide on thymic epithelium , leads to a deficient positive selection of CD4(+) T cells. Altogether, th ese in vitro and in vivo observations strongly indicate that the process of positive selection of immature thymocytes, and therefor-a the shaping of t he mature TCR repertoire is self-peptide specific.