Defects in the structure and expression of the genes for the T cell marker Rt6 in NZW and (NZB × NZW)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 deletion of one of the TCRβ genes in the same mouse strain and it is an intriguing possibility that these gene deletions arose by a common genetic mechanism. The Rt6 locus retained by the NZW mouse (designated Rt6-1) is polymorphic among inbred strains of laboratory mice. The NZW mouse shows several strain-specific restriction fragment length variants in this Rt6 locus and five amino acid substitutions occur in the predicted native Rt6 polypeptide of the NZW mouse relative to the corresponding polypeptides of NZB and BALB/c mice. Whereas transcript levels 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 retainedin this mouse strain. Moreover, reduced levels of Rt6 mRNA also occur in spleen and intestine of (NZB × NZW)F1 hybrid animals, indicating that F1 animals have inherited a dominant factor from the genetic background of the NZW mouse, resulting in low levels of Rt6 expression. It is conceivable that the alterations in the Rt6 genes of the NZW mouse and/or the factor(s) affecting defective Rt6 expression constitute part of the genetic contribution of the NZW mouse to the autoimmune lupus-like disease in (NZB × NZW)F1 animals. Interestingly, a deficiency of RT6 -expressing cells evidenced by reduced RT6 mRNA levels has previously also been observed in association with autoimmune disease in the BB-DP rat and NOD mouse animal models for autoimmune diabetes mellitus. The results presented here provide support for the hypotheses that a subset of RT6+ regulatory T cells confers protection to autoimmune disease in different animal models and that failure to develop this subset can result in enhanced susceptibility for autoimmune disease.