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 a ssociation with demyelinated lesions. Although the biological function of these cells remains to be established, it has been proposed that t hey are involved in the response to highly conserved antigens, such as heat shock proteins (hsp), expressed during tissue damage and thus ma y contribute to the development of an autoimmune response. Using polym erase chain reaction, we probed for the presence of T-cell receptor ga mma delta cells in fresh-frozen early autopsy brain tissue from patien ts with multiple sclerosis and patients with non-multiple sclerosis co nditions. The results demonstrated the presence of two major V-J combi nations of the T-cell receptor delta chain-V delta 2-J delta 3, V delt a 2=J delta 1-and we used a direct sequencing technique to determine w hether this gamma delta T-cell population was clonal or diverse. In ch ronic-active plaques from 9 patients with multiple sclerosis, we found a striking predominant gene rearrangement within the V delta 2-J delt a 3 T-cell receptor population that was not present in central nervous system tissue from patients with other neurological diseases. In cont rast, within the V delta 2-J delta 1 T-cell receptor population, a pre dominant 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 segme nt. These data strongly support the conclusion that within chronic-act ive 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 antig en.