Promiscuous Presentation and Recognition of Nucleosomal Autoepitopes in Lupus: Role of Autoimmune T Cell Receptor α Chain

Abstract

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-α and -β 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-α chain even when it paired with a TCR-β chain of irrelevant specificity. Several other disease-relevant Th clones and splenic T cells of lupus mice had similar properties. The TCR-α chains of these murine lupus Th clones shared related motifs and charged residues in their CDRs, and similar motifs were apparent even in TCR-α chains of human lupus Th clones. The lupus TCR-α 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-αβ+ 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).

MHC-Mismatched Chimerism Is Required for Induction of Transplantation Tolerance in Autoimmune Nonobese Diabetic Recipients

“…Consistently, we also observed that in chronic graft versus host disease (GVHD) recipients, there were alloreactive CD4 + T clones that possess autoreactivity and mediate autoimmune-like chronic GVHD (41). Our observations are also consistent with others' reports that autoreactive or alloreactive T cells can express promiscuous TCRs that are capable of responding to more than one Ag (13,(42)(43)(44)(45). In addition, recent reports indicate that some autoreactive T cells can express more than one TCR as a means of surviving thymic negative selection (46).…”

Low-Dose Peptide Tolerance Therapy of Lupus Generates Plasmacytoid Dendritic Cells That Cause Expansion of Autoantigen-Specific Regulatory T Cells and Contraction of Inflammatory Th17 Cells

“…The therapeutic benefit of H4 71-94 peptide is further augmented by degeneracy of lupus autoimmune system for nucleosomal epitopes: a single peptide epitope from a histone in the nucleosome can be recognized by multiple autoimmune T cells of lupus with diverse receptors, and conversely, a single autoimmune T cell can recognize structurally different histone peptides (12,14). Thus, a single peptide epitope can tolerize a spectrum of autoimmune Th cells and tolerizing one set of Th cells deprives help for multiple autoimmune B cells of lupus (tolerance spreading) (2,3).…”

“…Certain peptides in nucleosomal histones are dominant autoepitopes and spontaneous priming to these occurs in preclinical lupus (12,13). These epitopes are cross-reactively recognized by autoimmune Th cells, as well as B cells of lupus, and they can be promiscuously presented in the context of diverse MHC class II (MHC II) 4 alleles, like "universal epitopes" (2,(12)(13)(14). These unaltered, native peptide epitopes halt progression of lupus nephritis upon tolerization in high-dose soluble form and importantly for human therapy, the peptides are also effective in delaying/preventing lupus nephritis in subnanomolar doses (ϳ0.37 nM or 1 g), administered s.c. to lupus-prone SNF 1 mice (2,3,15).…”

Key Sequences Involved in the Spreading of the Systemic Autoimmune Response to Spliceosomal Proteins

“…In subsequent steps, the B cells present novel self determinants for a second tier of T-cell priming and finally, T cells provide help for a diversified B-cell response. This mechanism of collaboration between T and B cells specific for antigens noncovalently linked in a particle (also termed intermolecular-intrastructural help) might play an important role in the case of autoimmune response to chromatin [25,26]. It has been proposed that ab T-cell receptor bearing T cells specific for nucleosomal peptides are implicated in the production of anti-DNA antibodies.…”