MYELIN BASIC-PROTEIN SPECIFIC T-LYMPHOCYTE REPERTOIRE IN MULTIPLE-SCLEROSIS - COMPLEXITY OF THE RESPONSE AND DOMINANCE OF NESTED EPITOPES DUE TO RECRUITMENT OF MULTIPLE T-CELL CLONES

The human T cell response to the myelin basic protein (MBP) has been s tudied with respect to T cell receptor (TCR) usage, HLA class II restr iction elements, and epitope specificity using a total of 215 long-ter m MBP-specific T cell lines (TCL) isolated from the peripheral blood o f 13 patients with multiple sclerosis (MS) and 10 healthy donors. In m ost donors, the anti-MBP response was exceedingly heterogeneous. Using a panel of overlapping synthetic peptides spanning the entire length of human MBP, at least 26 epitopes recognized by human TCL could be di stinguished. The MBP domain most commonly recognized was sequence 80-1 05 (31% of MS TCL, and 24% of control TCL). Sequence 29-48 was recogni zed more frequently by control-derived TCL (24%) than by TCL from MS p atients (5%). The MBP epitopes were recognized in the context of DRB1 0101, DRB50101, DRB1*1501, DRB1*0301, DRB1*0401, DRB1*1402, and DRB3* 0102, as demonstrated using a panel of DR gene-transfected L cells. Th e TCR gene usage was also heterogeneous. Vbeta5.2, a peptide of which is currently being used in a clinical trial for treatment of MS patien ts, was expressed by only one of our TCL. However, within this complex pattern of MBP-specific T cell responses, a minority of MS patients w ere found to exhibit a more restricted response with respect to their TCL epitope specificity. In these patients 75-87% of the TCL responded to a single, patient-specific cluster of immunodominant T cell epitop es located within a small (20-amino acid) domain of MBP. These nested clusters of immunodominant epitopes were noted within the amino acids 80-105, 108-13 1, and 131-153. The T cell response to the immunodomina nt epitopes was not monoclonal, but heterogeneous, with respect to fin e specificity, TCR usage, and even HLA restriction. In one patient (H. K.), this restricted epitope profile remained stable for > 2 yr. The T CR beta chain sequences of TCL specific for the immunodominant region of HK are consistent with an oligoclonal response against the epitopes of this region (80-105). Further, two pairs of identical sequences we re established from TCL generated from this patient at different times (June 1990 and June 1991 ), suggesting that some TCL specific for the immunodominant region persisted in the peripheral repertoire. The pos sible role of persistent immunodominant epitope clusters in the pathog enesis of MS remains to be established.