DEFECTS IN THE STRUCTURE AND EXPRESSION OF THE GENES FOR THE T-CELL MARKER RT6 IN NZW AND (NZBXNZW)F1 MICE

Rt6 is a T cell-restricted GPI-anchored membrane protein and a member of the family of mono(ADP-ribosyl)transferases. One of the two murine Rt6 genes is deleted in NZW mice. This finding is reminiscent of the d eletion of one of the TCR beta genes in the same mouse strain and it i s an intriguing possibility that these gene deletions arose by a commo n genetic mechanism, The Rt6 locus retained by the NZW mouse (designat ed Rt6-1) is polymorphic among inbred strains of laboratory mice. The NZW mouse shows several strain-specific restriction fragment length va riants in this Rt6 locus and five amino acid substitutions occur in th e predicted native Rt6 polypeptide of the NZW mouse relative to the co rresponding polypeptides of NZB and BALB/c mice. Whereas transcript le vels of the two Rt6 genes appear to be normal in spleen and intestine of NZB mice, the corresponding tissues of NZW mice show reduced levels of transcripts from the Rt6 locus retained in this mouse strain, More over, reduced levels of Rt6 mRNA also occur in spleen and intestine of (NZB x NZW)F-1 hybrid animals, indicating that F-1 animals have inher ited a dominant factor from the genetic background of the NZW mouse, r esulting in low levels of Rt6 expression, It is conceivable that the a lterations in the Rt6 genes of the NZW mouse and/or the factor(s) affe cting defective Rt6 expression constitute part of the genetic contribu tion of the NZW mouse to the autoimmune lupus-like disease in (NZB x N ZW)F-1 animals. Interestingly, a deficiency of RT6-expressing cells ev idenced by reduced RT6 mRNA levels has previously also been observed i n association with autoimmune disease in the BB-DP rat and NOD mouse a nimal models for autoimmune diabetes mellitus. The results presented h ere provide support for the hypotheses that a subset of RT6(+) regulat ory T cells confers protection to autoimmune disease in different anim al models and that failure to develop this subset can result in enhanc ed susceptibility for autoimmune disease.