HLA-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice

In multiple sclerosis (MS) patients who carry the Class II major histocompa tibility (MHC) type HLA-DR2, T cells specific for amino acids 95-116 in the proteolipid protein (PLP) are activated and clonally expanded. However, it remains unclear whether these autoreactive T cells play a pathogenic role or, rather, protect against the central nervous system (CNS) damage. We hav e addressed this issue, using mice transgenic for the human MHC class II re gion carrying the HLA-DR2 (DRB1*1502) haplotype. After stimulating cultured lymph node cells repeatedly with PLP95-116, we generated 2 HLA-DR2-restric ted, PLP95-116-specific T-cell lines (TCLs) from the transgenic mice immuni zed with this portion of PLP. The TCLs were CD4(+) and produced T-helper 1 (Th1) cytokines in response to the peptide. These TCLs were adoptively tran sferred into RAG-2(-/-) mice expressing HLA-DR2 (DRB1*1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested ataxi c movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory foci primarily restricted to the cerebrum and cerebellum, in association with scattered demyelinating l esions in the deep cerebral cortex. These results support a pathogenic role for PLP95-116-specific T cells in HLA-DR2(+) MS patients, and shed Light o n the possible correlation between autoimmune target epitope and disease ph enotype in human CNS autoimmune diseases.