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International Immunology, Vol. 11, No. 9, 1563-1571, September 1999
© 1999 Japanese Society for Immunology

Augmentation of CTLA-4 expression by wortmannin: involvement of lysosomal sorting properties of CTLA-4

Shinji Oki, Takao Kohsaka and Miyuki Azuma

Department of Immunology, National Children's Medical Research Center, 3-35-31 Taishido, Setagaya-Ku, Tokyo 154-8509, Japan

Correspondence to: M . Azuma

CTLA-4 (CD152) is transiently induced on the cell surface of activated T cells and expression is limited at a low level. In this study, we investigated the possibility that phosphatidylinositol 3 kinase (PI 3-K) and other related PI kinases associated with the cytoplasmic domain of CTLA-4 are involved in intracellular trafficking and sorting of CTLA-4 protein. Treatment with micromolar concentrations of wortmannin (WN) for >4 h enhanced both cell-surface and intracellular CTLA-4 without affecting its transcriptional activities in a murine mastocytoma cell line transfected with the human CTLA-4 gene and normal activated CD4+ T cells. However, a more specific PI 3-K inhibitor, LY294002, failed to affect CTLA-4 expression, indicating that the action of WN is independent of conventional PI 3-K activities. WN down-regulated specific association of CTLA-4 with adaptor proteins and its endocytosis. The fact that lysosomotropic agents, ammonium chloride and monensin, enhanced CTLA-4 expression suggests that WN may also block lysosomal sorting and consequent degradation of CTLA-4. Co-localization of CTLA-4 and lysosome-associated membrane protein-1 detected by immunofluorescence microscopy indicates the actual lysosomal sorting of CTLA-4. Our data suggest the existence of WN-sensitive enzymes, which promote lysosomal sorting of CTLA-4. In addition to rapid endocytosis by clathrin-associated adaptor complex, a prompt sorting of CTLA-4 to lysosomes may be one of the regulatory mechanisms for managing CTLA-4 signals in intracellular trafficking pathways.

Keywords: CTLA-4 expression, endocytosis, lysosomal trafficking, post-translational regulation

Transmitting editor: K. Okumura


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