Detection of T-cell epitopes and modeling of DQ2 and DQ7 molecules using computational methods

摘要

The major histocompatibility complex(MHC)is a region of highly polymorphic genes and their products are expressed on the surfaces of a variety of cells.MHC genes play a central role in immune responses to protein antigens.This is because antigen-specific T lymphocytes do not recognize antigens in free or soluble form but instead recognize portions of protein antigens(i.e peptides)that are non-covalently bound to MHC gene products.MHC molecules provide a system for displaying antigenic peptides to T-cells.This allows T-cells to survey the body for the presence of peptides derived from foreign proteins.There are two different types of MHC gene products,called class-I and class-II MHC molecules.This study is focused on the class-II MHC molecules which assist in immune surveillance by presenting peptide fragments of potential antigens circulating T cells.They are cell surface glycoproteins composed of high polymorphic alpha and beta subunits(approx 30000 molecular weight for each subunit).MHC-II molecules bind antigenic peptides,usually 9-25 amino acids length,and display them on the cell surface,where the MHC/peptide complex can be recognized by TCR of CD4+ T-cells.CD4+ T cells are key components of the protective immune response to infectious pathogens,under certain circumstances they may also be responsible for the deleterious effects related to a number of autoimmune diseases and for transplantation reactions involving both cellular and organ allogeneic grafts.Recently,the three-dimensional structure of a human insulin peptide-HLA-DQ8 complex was determined using X-ray crystallography.The main characteristics of the DQ8 molecule are:an antigen binding groove that is opened at both ends,allowing long peptides to bind and four residue-binding pockets(P1,P4,P6 and P9).Determing which peptides bind to a specific MHC-II molecule is fundamental to understand the basis of immunity and permits the development of peptide-based or other defined antigen-based vaccines.In this work we tried to define T-cell epitopes of the La autoantigen which is involved in systemic autoimmune diseases mostly with primary Sjogren's syndrome(pSS)and Systemic Lupus Erythematosus(SLE).The definition of these epitopes was based on a sequence pattern common to T-cell epitopes the MHCPEP database and the TEPITOPE program.The pattern which we have used revealed a number of epitopes within the primary structure of La autoantigen.Among these epitopes only a few fit properly into the modeled DQ2 and DQ7 groove.We also performed energy minimization to MHC/peptide complex using the X-PLOR program.