T cell receptor α-chain repertoire of pathogenic autoantibody-inducing T cells in lupus mice

The production of pathogenic anti-DNA autoantibodies in mice with lupus nephritis is dependent on special autoimmune Th cells that can also transfer the disease into preautoimmune mice. In previous work, these pathogenic Th cells were cloned and their TCR β-chains were sequenced to reveal a recurrent motif of anionic residues in their CDR3 loops. Accordingly, approximately half of the Th clones were found to be specific for nucleosomal Ag that contain cationic residues. Herein, we analyzed the TCR α-chain repertoire of 15 of these pathogenic Th clones and found them to be heterogeneous, even among the nucleosome-specific Th clones. Most of these autoimmune TCR α-chains contained anionic residues in their CDR3 in addition to cationic residues. Therefore, these pathogenic Th clones of lupus probably recognize epitopes with mixed charge runs that are derived from autoantigens, such as histone-DNA complexes. Interestingly, the Vα gene segments used by 10 of these Th clones derived from the (SWR x NZB)F₁ lupus mice differed from previously reported sequences indicating that they were new members or alleles of the respective Vα gene family. One of the Th clones used a gene from an entirely new murine Vα gene family, identified here as Vα23, which consisted of approximately two members that were conserved among strains with different Vα haplotypes. Knowledge of the primary structure of the TCR expressed by these pathogenic Th clones of lupus would help in the analysis of their antigenic specificities and also would be essential for studying their regulation in transgenic mice carrying these autoimmune TCR genes.