A regulatory role for cytoplasmic YVKM motif in CTLA-4 inhibition of TCR signaling

CTLA-4 negatively regulates TCR signaling, although the molecular basis for this effect has yet to be elucidated. The cytoplasmic YVKM motif, white bi nding to phosphatidylinositol 3-kinase, SHP-2 and the AP-1/AP-2 clathrin ad aptor complexes, has been reported to play no role in CTLA-4 function. In c ontrast, in this study We demonstrate that, although not essential, the YVK M motif contributes to optimal CTLA-4 blockage of TCR zeta or combined TCR zeta /CD28 signaling. Significantly, dependency on the YVKM motif varied wi th the mode of anti-receptor presentation, where soluble antibody ligation was more dependent on the presence of the motif than immobilized antibody. Previous studies have mainly relied on the use of immobilized, antibody. Ne ither SHP-2 binding, alterations in TCR zeta chain phosphorylation, nor ZAP -70 recruitment was involved in CTLA-4 wild-type or mutant inhibition. Over all, our findings clearly implicate the YVKM motif in optimal CTLA-4 functi on.