Junctional region sequences of T-cell receptor β-chain genes expressed by pathogenic anti-DNA autoantibody-inducing helper T cells from lupus mice: Possible selection by cationic autoantigens

We rescued from the spleens of 10 (SWR × NZB)F₁ (SNF₁) mice with lupus nephritis the T cells that were activated in vivo and cloned 268 T-cell lines and hybridomas. Only 12% of these T-cell clones had the functional ability to preferentially augment the production of pathogenic anti-DNA autoantibodies. Among these, 16 helper T-cell (T_h-cell) clones that were mostly CD4₁ and had the strongest autoantibody-inducing ability were analyzed for T-cell receptor (TCR) β-chain gene usage. Seven of the 16 Th-cell clones expressed β-chain variable region (V_β1) V_β (8.2 or 8.3) genes and three expressed V_β4, whereas two clones each used V_β1 or V_β2 or Vβ14 gene, suggesting some restriction in TCR gene usage. Although heterogeneous, the V-D-J junctional region sequences of TCR β-chain genes used by these T_h-cell clones Invariably encoded one or more negatively charged residues (aspartic or glutamic acid) that had been generated in most cases by unspecified nucleotide (N) additions. Representative pathogenic autoantibody-inducing T_h-cell clones could rapidly induce the development of lupus nephritis when injected into young prenephritic SNF, mice. The pathogenic autoantibody-inducing T_h cells expressing the anionic residues in their TCR β-chain junctions (complementarity-determining region CDR3) were probably selected by some cationic autoantigenic peptide presented by the anti-DNA B cells they preferentially helped. These results offer a clue regarding the nature of the primary autoantigen that may drive the pathogenic autoimmune response in lupus.