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J. Exp. Med.,
Volume 187, Number 3, February 2, 1998 367-378
Chain
By
From the * Department of Medicine and the Department Microbiology-Immunology, and Multipurpose
Arthritis Center, Northwestern University Medical School, Chicago, Illinois 60611, and 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- Cytel
Corporation, San Diego, California 92121
and -
chain genes of a representative, pathogenic autoantibody-inducing Th clone specific for the nucleosomal core histone peptide H471-94 into TCR-negative recipient cells. Although the autoimmune TCRs were originally derived from SNF1 (I-Ad/q) mice,
the transfectants could recognize the nucleosomal autoepitope presented by APC-bearing I-A
molecules of all haplotypes tested, as well as human DR molecules. Competition assays indicated that the autoepitopes bound to the MHC class II groove. Most remarkably, MHC-unrestricted recognition of the nucleosomal peptide epitope was conferred by the lupus TCR-
chain even when it paired with a TCR- chain of irrelevant specificity. Several other disease-relevant Th clones and splenic T cells of lupus mice had similar properties. The TCR- chains
of these murine lupus Th clones shared related motifs and charged residues in their CDRs, and
similar motifs were apparent even in TCR- chains of human lupus Th clones. The lupus
TCR- chains probably contact the nucleosomal peptide 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-+ Th cells are expanded in systemic lupus erythematosus. These results have implications regarding thymic selection and peripheral expansion of nucleosome-specific T cells in lupus. They also suggest that universally tolerogenic epitopes could be designed for therapy of lupus patients with diverse HLA alleles. We propose to designate nucleosomes and other antigens
bearing universal epitopes "Pantigens" (for promiscuous antigens).
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