[A study on mechanisms of thymic selection by intrathymic administration of antigenic peptides]

Abstract

In the process of T cell differentiation thymocytes undergo positive and negative selections. The positive and negative selections result from interactions between the T cell antigen receptor (TCR) and self peptides presented by the major histocompatibility complex (MHC) molecules. Positive selection generates functional T cells restricted to the self-MHC. Negative selection eliminates or anergies T cells bearing self reactive TCR with high affinity to self peptides plus MHC. In this study, differentiation and selection of thymocytes were analyzed using bone marrow chimeras. It was demonstrated that differentiation of CD4+CD8+ thymocytes to CD4+ or CD8+ mature thymocytes occurred between 12 and 16 days post bone marrow transplantation. When pigeon cytochrome c 43-58 related peptide antigens were injected intrathymically 13 days after bone marrow transplantation, various changes were observed in resultant T cell repertoire. Intrathymic injection of peptides with high affinity to the MHC class II resulted in specific inhibition of T cell responses to the peptides, whereas injection of peptides with low affinity to the MHC induced no alteration. Furthermore, no modification of T cell responses was observed, when these peptides were administered after 14 days post BMT. The present findings demonstrate that when peptides with high affinity to the MHC class II molecules are administered intrathymically at a critical stage of thymocyte differentiation, negative selection is induced in a manner of one peptide vs one T cell clone.