PROMISCUOUS PRESENTATION AND RECOGNITION OF NUCLEOSOMAL AUTOEPITOPES IN LUPUS - ROLE OF AUTOIMMUNE T-CELL RECEPTOR-ALPHA CHAIN

T cells specific for nucleosomal autoepitopes are selectively expanded in lupus mice and these Th cells drive autoimmune B cells to produce pathogenic antinuclear antibodies. We transfected the TCR-alpha and -b eta chain genes of a representative, pathogenic autoantibody-inducing Th clone specific for the nucleosomal core histone peptide H4(71-94) i nto TCR-negative recipient cells. Although the autoimmune TCRs were or iginally derived from SNF1 (I-A(d/q)) mice, the transfectants could re cognize the nucleosomal autoepitope presented by APC-bearing I-A molec ules of all haplotypes tested, as well as human DR molecules. Competit ion assays indicated that the autoepitopes bound to the MHC class II g roove. Most remarkably, MHC-unrestricted recognition of the nucleosoma l peptide epitope was conferred by the lupus TCR-alpha chain even when it paired with a TCR-beta chain of irrelevant specificity. Several ot her disease-relevant Th clones and splenic T cells of lupus mice had s imilar properties. The TCR-alpha chains of these murine lupus Th clone s shared related motifs and charged residues in their CDRs, and simila r motifs were apparent even in TCR-alpha chains of human lupus Th clon es. The lupus TCR-alpha chains probably contact the nucleosomal peptid e complexed with MHC with relatively high affinity/avidity to sustain TCR signaling, because CD4 coreceptor was not required for promiscuous recognition. Indeed, pathogenic autoantibody-inducing, CD4-negative, TCR-alpha beta(+) Th cells are expanded in systemic lupus erythematosu s. These results have implications regarding thymic selection and peri pheral expansion of nucleosome-specific T cells in lupus. They also su ggest that universally tolerogenic epitopes could be designed for ther apy of lupus patients with diverse HLA alleles. We propose to designat e nucleosomes and other antigens bearing universal epitopes ''Pantigen s'' (for promiscuous antigens).