Terminal deoxynucleotidyl transferase deficiency decreases autoimmune disease in MRL-Fas(lpr) mice

The neonatal Ab and TCR repertoires are much less diverse, and also very di fferent from, the adult repertoires due to the delayed onset of terminal de oxynucleotidyl transferase (TdT) expression in ontogeny. TdT adds nontempla ted N nucleotides; to the junctions of Igs and TCRs, and thus its absence r emoves one of the major components of junctional diversity in complementari ty-determining region 3 (CDR3). We have generated TdT-deficient MRL/(lpr), Fas-deficient (MRL-Fas(lpr)) mice, and show that they have an increased lif espan, decreased incidence of skin lesions, and much lower serum levels of anti-dsDNA, anti-chromatin, and IgM rheumatoid factors. The generalized hyp ergammaglobulinemia characteristic of MRL-Fas(lpr) mice is also greatly red uced, as is the percentage of CD4(-)CDS(-)B220(+) (double-negative) T cells . IgG deposits in the kidney are significantly reduced, although evidence o f renal disease is present in many mice at 6 mo. CDR3 regions of both IgH a nd TCR from peripheral lymphocytes of MRL-Fas(lpr) mice are shorter in the absence of TdT, and there is a paucity of arginines in the IgH CDR3 regions of the MRL-Fas(lpr) TdT(-/-) mice. Because the amelioration of symptoms is so widespread, it is likely that the absence of N regions has more of an a ffect than merely decreasing the precursor frequency of anti-dsDNA B cells. Hence, either the T or B cell repertoires, or more likely both, require N region diversity to produce the full spectrum of autoimmune lupus disease.