CYTOTOXIC T-LYMPHOCYTE-ASSOCIATED MOLECULE-4, A HIGH AVIDITY RECEPTORFOR CD80 AND CD86, CONTAINS AN INTRACELLULAR-LOCALIZATION MOTIF IN ITS CYTOPLASMIC TAIL

CD28 and CTLA-4, T cell receptors for B7-1 (CD80) and B7-2 (CD86) mole cules on antigen-presenting cells, transmit costimulatory signals impo rtant for optimal T cell activation. Despite sharing sequence homology and common ligands, these receptors have distinct binding properties and patterns of expression. The function of CTLA-4 during T cell activ ation is not well understood, although an important role is suggested by complete amino acid sequence conservation of its cytoplasmic tail i n all species studied to date. We report here a role of the cytoplasmi c tail of CTLA-4 in regulating its subcellular localization and cell s urface expression. In activated human peripheral blood T cells, or in several transfected or transduced cell types, CTLA-4 is not primarily a cell surface protein, but rather is localized intracellularly in a r egion which overlaps the Golgi apparatus. Transfer of 11 cytoplasmic r esidues, (161)TTGVYVKMPPT, from the CTLA-4 cytoplasmic tail to the hom ologous position in CD28 was sufficient to confer intracellular locali zation. Mutation of the tyrosine residue (Tyr(165)) in this motif to p henylalanine resulted in increased sur face expression of CTLA-4. Thus , the subcellular localization of CTLA-4 is controlled by a tyrosine-c ontaining motif within its cytoplasmic domain. Contained within this m otif is a binding site for SH2 domains of the p85 subunit of phosphati dylinositol 3-kinase.