Diversity and dynamics of the T-cell response to MBP in DR2+ve individuals

Abstract

It is generally accepted that multiple sclerosis (MS) is mediated by autoreactive T cells and that myelin basic protein (MBP) is one of the target autoantigens. The T-cell response to MBP has been analysed extensively, largely through the use of T-cell lines (TCL) and T-cell clones (TCC), and to date, three immunodominant regions (13-32, 84-103 and 144-163) have been described. However, given that TCL may represent a skewed pattern of peptide reactivity, we have developed a kinetic response assay in which the proliferation of peripheral blood mononuclear cells (PBMC) from MS patients and healthy individuals was measured directly against a panel of peptides spanning the full length of human MBP. Furthermore, PBMC from each subject were tested three times over the course of 18 months. A high proportion of MS patients exhibited a significant response to eight MBP regions (1-24, 30-54, 75-99, 90-114, 105-129, 120-144, 135-159 and 150-170). TCC were subsequently generated from MS subjects and were used to further define the epitope recognized in each case. Overall, normal individuals recognized significantly fewer peptides. In addition, we noted that the T-cell recognition of any one peptide can fluctuate, appearing at one time point, regressing, and subsequently reappearing at a later date. This study provides new insight into the recognition profile and dynamics of myelin-antigen-specific T cells in MS.