Développement intrathymique des lymphocytes T : le rôle des peptides du soi dans le processus de sélection positive

Abstract

Au cours du developpement des lymphocytes T αβ, le processus de selection positive requiert l' interaction du recepteur de l' antigene (TCR) avec les molecules du complexe majeur d' histocompatibilite (CMH) exprimees a la surface des cellules epitheliales du cortex thymique. On s' est longtemps demande si l' interaction TCR-CMH est intrinsequement suffisante ou si les peptides du soi complexes aux molecules du CMH remplissent un role particulier lors de la selection positive. L' utilisation d' animaux genetiquement modifies, presentant des alterations des processus d' appretement et/ou de presentation de l' antigene a permis de montrer que la diversite des peptides du soi presentes par les molecules du CMH a un impact direct sur l' efficacite du developpement des lymphocytes CD4+ et CD8+. L' ensemble de ces resultats experimentaux indique que le developpement intrathymique des lymphocytes T αβ, et par consequent l' elaboration du repertoire T fonctionnel, est fondee sur la reconnaissance des peptides du soi au cours du processus de selection positive.

The generation of mature alphabeta T cells is directly dependent on molecular interactions between the TCR and the MHC interaction during intrathymic development. Pioneering experiments using mice bearing spontaneous MHC class I molecules mutations, which affect peptide binding but not the TCR/MHC interaction, have suggested an important role for self-peptides in the development of mature CD8+ T lymphocytes. This idea received considerable support when mice deficient for MHC class I molecules were used: fetal thymic organ culture experiments demonstrated that all the peptides able to restore surface expression of MHC class I molecules do not necessarily restore the development of CD8+ thymocytes. Additionally, a mixture of different peptides was found to be more efficient than individual peptides in driving positive selection, suggesting that self complexity controls optimal T cell positive selection. Recent in vivo 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 molecules, which display a very restricted set of self-peptide on thymic epithelium, leads to a deficient positive selection of CD4+ T cells. Altogether, these in vitro and in vivo observations strongly indicate that the process of positive selection of immature thymocytes, and therefore the shaping of the mature TCR repertoire, is self-peptide specific.