ABSTRACT
The human PDC-E2 163-176 peptide (GDLLAEIETDKATI) is an immunodominant autoreactive T-cell epitope in patients with primary biliary cirrhosis (PBC), restricted by HLA DRB4*0101. We have previously reported that the ExDK sequence is essential for recognition of this epitope and identified 1 mimicry peptide, Escherichia coli PDC-E2 peptide (EQSLITVEGDKASM), which can activate human PDC-E2 163-176 peptide-reactive T-cell clones. In the present study, to further investigate mimicry peptides possibly involved in PBC, we generated 13 different T-cell clones reactive to the human PDC-E2 163-176 peptide following repeated in vitro stimulation of peripheral T lymphocytes with the human PDC-E2 163-176 peptide (native peptide) and tested for the reactivity of these T-cell clones to 30 different mimicry peptides derived from various self- and nonself proteins that have an ExDK-sequence. We found 7 mimicry peptides derived from microbial proteins that can activate at least 1 of these T-cell clones; 7 of 7 T-cell clones from patients with PBC and 2 of 6 T-cell clones from healthy subjects were activated by at least 1 to 6 different mimicry peptides. Two of 6 T-cell clones from healthy subjects were activated by specific mimicry peptides more strongly than by the native peptide, and 2 of 6 T-cell clones from healthy subjects were not activated by any mimicry peptides tested. Thus, the pattern and degree of activation by mimicry peptides differed in each T-cell clone, indicating the presence of a diverse spectrum of autoreactive T cells that are reactive to a single minimal epitope of the human PDC-E2 163-176 peptide.
Subject(s)
Immunodominant Epitopes , Liver Cirrhosis, Biliary/immunology , Molecular Mimicry , Peptide Fragments/immunology , Pyruvate Dehydrogenase Complex/immunology , T-Lymphocytes/immunology , Cell Division/drug effects , Clone Cells/cytology , Clone Cells/drug effects , Clone Cells/immunology , Clone Cells/metabolism , Cytokines/biosynthesis , Dihydrolipoyllysine-Residue Acetyltransferase , Humans , Peptide Fragments/pharmacology , Pyruvate Dehydrogenase Complex/pharmacology , T-Lymphocytes/classification , T-Lymphocytes/cytology , T-Lymphocytes/metabolismABSTRACT
The T cell repertoire is shaped by positive and negative selection of thymocytes through the interaction of alpha/beta-T cell receptors (TCR) with self-peptides bound to self-major histocompatibility complex (MHC) molecules. However, the involvement of specific TCR-peptide contacts in positive selection remains unclear. By fixing TCR-beta chains with a single rearranged TCR-beta irrelevant to the selecting ligand, we show here that T cells selected to mature on a single MHC-peptide complex express highly restricted TCR-alpha chains in terms of Valpha usage and amino acid residue of their CDR3 loops, whereas such restriction was not observed with those selected by the same MHC with diverse sets of self-peptides including this peptide. Thus, we visualized the TCR structure required to survive positive selection directed by this single ligand. Our findings provide definitive evidence that specific recognition of self-peptides by TCR could be involved in positive selection of thymocytes.
