PubMed · 9238508
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T Elliott. 1997. Transporter associated with antigen processing.. https://pubmed.ncbi.nlm.nih.gov/9238508/
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Liposomes have the well-known ability to channel protein and peptide antigens into the MHC class II pathway of phagocytic antigen-presenting cells (APCs) and thereby enhance the induction of antibodies and antigen-specific T cell proliferative responses. Liposomes also serve as an efficient delivery system for entry of exogenous protein and peptide antigens into the MHC class I pathway and thus are very efficient inducers of cytotoxic T cell responses. Soluble antigens that are rendered particulate by encapsulation in liposomes are localized both in vacuoles and in the cytoplasm of bone marrow-derived macrophages. Utilizing fluorophore-labeled proteins encapsulated in liposomes we have addressed the question of how liposomal antigens enter the MHC class I pathway. After phagocytosis of the liposomes, the fluorescent liposomal protein and liposomal lipids enter the cytoplasm where they are processed by the proteasome complex. The processed liposomal protein is then transported via the TAP complex into the endoplasmic reticulum and the Golgi complex. Both the liposomal lipids and the liposomal proteins appear to follow the same intracellular route and they are processed as a protein-lipid unit. In the absence of a protein antigen (empty liposomes), there is no organelle-specific localization of the liposomal lipids. In contrast, when a protein is encapsulated in these liposomes, the distribution of the liposomal lipids is dramatically affected and the liposomal lipids localize to the trans-Golgi area. Localization of the protein in the trans-Golgi area requires liposomal lipids. Similarly, for the localization of liposomal lipids in the trans-Golgi area, there is an obligatory requirement for protein. Therefore, the intracellular trafficking patterns of liposomal lipids and liposomal protein are reciprocally regulated. Presence of both liposomal lipids and liposomal protein in the trans-Golgi therefore facilitates the entry of liposomal antigens into the MHC class I pathway. It is also possible that liposomal lipids are presented to T cells via the recently described CD1 pathway for lipid antigens. Because liposome-formulated vaccines have the potential to stimulate antibody as well as cellular immune responses to protein and lipid components, this approach could prove to be extremely useful in designing vaccine strategies.
The transporter associated with antigen processing (TAP) comprises two structurally related subunits, TAP1 and TAP2, that form stable complexes in endoplasmic reticulum (ER) membranes. TAP complexes function in the translocation of peptides from the cytosol into the ER lumen for presentation by major histocompatibility complex class I molecules. Each TAP subunit contains an N-terminal membrane-spanning region with multiple membrane-spanning segments, and a C-terminal, cytosolic nucleotide binding region. To study the nature of the interactions occurring on the cytosolic face of TAP1/TAP2 complexes, we investigated quaternary associations mediated by two C-terminal fragments of human TAP1 (T1c, residues 452-748 and T1ctr, residues 472-748) and two C-terminal fragments of human TAP2 (T2c, residues 399-686 and T2ctr, residues 433-686). Each of these constructs contains the core nucleotide binding region as well as a long or short N-terminal extension. We show stable complex formation between T1c and T2c but not between T1ctr and T2ctr. The mechanistic implications of these results are discussed. We also show that each of the constructs except T1ctr interacts with wild type TAP1 and TAP2, indicating possibilities for homodimerization of TAP1 and TAP2, or of oligomerization of TAP1/TAP2 heterodimers on membranes.
The transporter associated with antigen processing (TAP) binds peptides in its cytosolic part and subsequently translocates the peptides into the lumen of the endoplasmic reticulum (ER), where assembly of major histocompatibility complex (MHC) class I and peptide takes place. Tapasin is a subunit of the TAP complex and binds both to TAP1 and MHC class I. In the absence of tapasin, the assembly of MHC class I in the ER is impaired, and the surface expression is reduced. To clarify the function of tapasin in the processing of antigenic peptides, we studied the interaction of peptide and TAP, peptide transport across the membrane of the ER, and association of peptides with MHC class I molecules in the microsomes derived from tapasin mutant cell line 721.220, its sister cell line 721.221 expressing tapasin, and their HLA-A2 transfectants. The binding of peptides to TAP in tapasin mutant 721.220 cells was significantly diminished in comparison with 721.221 cells. Impaired peptide-TAP interaction resulted in a defective peptide transport in tapasin mutant 721.220 cells. Interestingly, despite the diminished peptide binding to TAP, the transport rate of TAP-associated peptides was not significantly altered in 721.220 cells. After transfection of tapasin cDNA into 721.220 cells, efficient peptide-TAP interaction was restored. Thus, we conclude that tapasin is required for efficient peptide-TAP interaction.