MULTIPLE-SCLEROSIS - LIMITED DIVERSITY OF THE V-DELTA-2-J-DELTA-3 T-CELL RECEPTOR IN CHRONIC ACTIVE LESIONS

T lymphocytes bearing the gamma delta T-cell receptor have been found in the central nervous system of patients with multiple sclerosis in association with demyelinated lesions. Although the biological function of these cells remains to be established, it has been proposed that they are involved in the response to highly conserved antigens, such as heat shock proteins (hsp), expressed during tissue damage and thus may contribute to the development of an autoimmune response. Using polymerase chain reaction, we probed for the presence of T-cell receptor gamma delta cells in fresh-frozen early autopsy brain tissue from patients with multiple sclerosis and patients with non-multiple sclerosis conditions. The results demonstrated the presence of two major V-J combinations of the T-cell receptor delta chain-V delta 2-J delta 3, V delta 2=J delta 1-and we used a direct sequencing technique to determine whether this gamma delta T-cell population was clonal or diverse. In chronic-active plaques from 9 patients with multiple sclerosis, we found a striking predominant gene rearrangement within the V delta 2-J delta 3 T-cell receptor population that was not present in central nervous system tissue from patients with other neurological diseases. In contrast, within the V delta 2-J delta 1 T-cell receptor population, a predominant rearrangement pattern was detected in only 1 of the multiple sclerosis patients. The sequence of the predominant V delta 2-J delta 3 gene rearrangement was confirmed by cloning and sequencing the gene products from 1 multiple sclerosis patient. This junctional region was characterized by shortened D delta and J delta segments, few N region insertions, and use of the third reading frame of the D delta 3 segment. These data strongly support the conclusion that within chronic-active multiple sclerosis lesions, T cells bearing the V delta 2-D delta 3-J delta 3 receptor might have arisen as a response to a common antigen.