Pathogenic viruses pose a world-wide public health problem of great importance. The immune system has evolved strategies to combat viral infections, an important one being the detection and illimination of virally infected host-cells by cytotoxic T lymphocytes (CTLs). The T lymphocytes antigen receptor (TCR) recognizes virally infected cells by detecting peptide fragments of virus, expressed on the surface of cells in complexes with self-MHC (Major Histocompatibility Complex) molecules. How T cells distinguish between viral-peptide and self- peptides is unclear. However, the impairment of this ability can lead to the development of autoimmunity. The TCR repertoire displayed by CTLs is determined through the development of T cells in the thymus. Within the thymus, T cell development selects for cells that recognize peptide antigen presented by self-MHC, but are not reactive to MHC/self-peptide complexes. However, we have shown that the recognition of self-peptide/self-MHC complexes, expressed on the surface of thymic stromal cells, is required to trigger the development of cells destined to become CTLs.
We aim to determine how thymic self-peptides shape the antigenic repertoire of CTLs. Using a combination of chromatographic and mass-spectroscopic techniques, we will purify and sequence self-peptides for thymic-MHC molecules, which are recognized by CTLs specific for two different pathogenic viruses, Influenza (IF) and Lymphocytic Choriomeningitis virus (LCMV). By adding synthetic self-peptides to a fetal thymic organ culture (FTOC) system utilizing TAP1- mice, we will examine how self-peptides specific for a given TCR (anti-IF peptide or anti-LCMV peptide) trigger the differentiation of CTLs with the same TCR. Using a similar FTOC system, we will also study how the recognition of the thymic self-peptides gives rise to the development of the diverse array of antigenic specificity~s displayed by CTLs. Analysis of mice, with impaired peptidase activity and impaired thymic selection of CTLs, will allow us to identify which thymic self-peptides trigger the development of CTLs. This proposal seeks to understand how the recognition of self during development gives rise to an immune system which can respond specifically to non-self pathogens. It is hoped that this study lead to a better understanding of how autoimmune disease can be prevented as well as facilitate our understanding of how antiviral immunity develops.
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