Deletion of signaling molecule genes resembling the cytoplasmic domain of Igbeta in autoimmune-prone mice

Abstract

The P8.6 gene is encoded upstream of the mouse TCR Valpha1 gene in the anti-sense strand and its gene product contains the proline-rich region and tyrosine-isoleucine (Y-I) motif, which are consensus sequences for the SH2 and SH3 binding motifs respectively. It was found that this protein is highly homologous to Igbeta. We also found that the P8.6 protein associates with a 170 kDa phosphorylated protein in vivo. To examine the polymorphism of the P8.6 gene, we carried out a single-strand conformation polymorphism analysis and found that the P8.6 gene comprises a family of at least 13 independent genes arising from single or multiple mutations. The mutated P8.6 gene with the Y-L motif was deleted, especially in NZW and BXSB mice, whereas normal BALB/c mice have a P8.6 gene bearing both the Y-I and Y-L motifs, suggesting a dysregulation in signaling through the B cell receptor or TCR in these two autoimmune mice. Functional analysis using transfectant cells carrying P8.6-1 (Y-I motif) and P8.6-3 (Y-L motif) clearly demonstrated that P8.6-3 gene inhibited the signal transduction upon the stimulation of ionomycin and cell growth. The TANYSNI sequence has been proposed as the immunoreceptor tyrosine-based inhibitory motif, this motif is replaced by AANYSNI in the NZW mice. In conclusion, some P8.6 are deleted in particular autoimmune-prone mice.