Search

We have investigated whether the normal immune system contains T cells that are able to recognize T cell receptor (TcR) determinants of autologous autoantigen-specific T cells. The T cell clone HW.BP3, specific for myelin basic protein (MBP) was isolated from a healthy donor. HW.BP3 is restricted by HLA-DR2a, and reacts to human MBP 139-153. The expressed alpha beta TcR genes of HW.BP3 were cloned and sequenced, and the sequences analyzed for potential T cell epitopes. Two synthetic peptides, one from the VDJ beta junctional (beta 1) and one from the V beta region (beta 2) of the TcR of HW.BP3, were used to select four TcR peptide-specific T cell lines from the donor of HW.BP3. All anti-TcR lines had the phenotype CD3+/CD4+/HLA-DR+/CD25+/CD45RO+, and recognized the antigen in the context of HLA-DR. Three anti-TcR lines, which had been selected for reactivity to peptide beta 1, recognized exclusively this peptide restricted by HLA-DR2b. One anti-TcR line, selected for peptide beta 2, responded to both peptides beta 1 and beta 2 when presented by autologous blood mononuclear cells, but not by HLA-DR2a- or HLA-DR2b-transfected L cells. All TcR peptide-specific T cell lines were efficiently cytotoxic. They specifically lysed autologous macrophages or HW.BP3 line cells in the presence of exogenous peptide antigen. In contrast, HW.BP3 did not present endogenous TcR peptides to the anti-TcR lines. The results demonstrate that the normal human immune system contains not only autoantigen-specific T cells, but also T cells that recognize antigenic determinants of autologous autoreactive TcR.

T cell receptor (TcR) alpha and beta nucleotide sequences involved in the human autoreactivity to myelin basic protein (MBP) were studied by screening cDNA libraries derived from 11 independent T lymphocyte clones (TCC) established from multiple sclerosis patients and healthy donors. The TCC with defined MBP peptide specificity and HLA-DR restriction expressed multiple TcR. Even TCC recognizing the same human MBP peptide [amino acids (aa) 139-153] in identical or very similar HLA-DR context expressed diverse TcR. Two TCC which recognized peptide aa 139-153 equally well in the context of both HLA-DR2a and -DR1 molecules used distinct TcR alpha but identical beta chains. The knowledge of TcR beta and TcR alpha chain sequences of human MBP-specific T cells will allow studies correlating structure and function of TcR and their targets in MBP autoreactivity. This may have an impact on the development of immunotherapies in multiple sclerosis.