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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Immunobiology Study Section (IMB)
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Macchiarini, Francesca
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University of Chicago
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