Restricted T-cell receptor V beta gene usage by myelin basic protein-specific T-cell clones in multiple sclerosis: predominant genes vary in individuals.

Abstract

Recent studies in experimental autoimmune encephalomyelitis as a model for multiple sclerosis (MS) have demonstrated limited heterogeneity in T-cell antigen receptors (TCR) specific for myelin basic protein (MBP). To investigate restricted j3-chain variable-region (Vp) gene usage in humans, we analyzed TCR gene rearrangements in two lines and 34 MBP-specific T-cell clones that were isolated from five MS patients and two healthy subjects. The T cells were characterized for their specificity to MBP epitopes and HLA-restricting molecules. We demonstrate here that MBP-specific T-cell clones from these different MS patients and healthy individuals, in contrast to T cells from rodents, display a more diverse (7) and Lewis rats (9). These studies raised the possibility of limited TCR heterogeneity by T cells mediating the autoimmune disease in humans and the possible immune intervention by monoclonal antibodies to TCR elements as an approach to therapy. We therefore investigated the TCR (3-chain variable-region (Vp) genes associated with the reactivity of MBP-specific T-cell clones in humans, both as possible pathogenic T cells in MS and as a prototypic T-cell-mediated response to a system-specific human selfantigen. Here, we present an analysis of Va gene usage by long-term lines and by 34 clones specific to MBP, which were isolated from five MS patients, and we present results suggesting a TCR heterogeneity among MBP-sp'ecific T cells from different individuals but a limited Vp gene usage among MBP-specific T cells of the same individual.

Binding of myelin basic protein peptides to human histocompatibility leukocyte antigen class II molecules and their recognition by T cells from multiple sclerosis patients.

“…Although the DRBl * 1501 haplotype is associated with the highest relative risk of MS, other HLA class II alleles are overrepresented among certain ethnic groups of MS patients: DR4 in Southern Italians ( 15) and Arabs (16) and DR1 3 in Japanese (17) and Mexicans ( 18). In contrast to the well-established association between HLA genes and MS, the association ofTCR genes, either in the germline ( 19,20) or in the hMBP-specific peripheral T cell repertoire (21)(22)(23)(24)(25), with MS is still unclear.…”

Treatment of experimental encephalomyelitis with a novel chimeric fusion protein of myelin basic protein and proteolipid protein.

“…Two hydrophilic regions of PLP, residues 30-49 and 180-199, were recently demonstrated to be immunodominant regions recognized by human peripheral T cell populations after primary in vitro stimulation with native PLP (33). However, results from several laboratories have further revealed a marked heterogeneity of human T cell proliferative responses to MBP and PLP with respect to epitope recognition, MHC restriction, and T cell receptor usage (13, 28,30,[34][35][36][37][38][39][40][41][42][43][44][45][46][47]. Furthermore, there is evidence for progressive diversification of the T cell repertoire during the course of autoimmune disease.…”

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.

“…A key issue raised by these studies is the heterogeneity of the human T cell response to MBP. Unlike the response to MBP in inbred animal strains, there seems to be a broader diversity ofTCR usage and epitope specificity in MS patients (10)(11)(12)(13)(14)(15)(16)(17).…”