title: MHC class II-associated invariant chain peptide replacement by T cell epitopes: engineered invariant chain as a vehicle for directed and enhanced MHC class II antigen processing and presentation.
abstract: Proteolysis of the invariant chain (li) leads to the generation of abundant MHC class II-associated invariant chain peptides (CLIP), which bind in the MHC class II binding groove via supermotifs in a manner similar to that of antigenic peptides. We have engineered an li vector with the capacity to express any antigenic peptide of interest instead of CLIP, for T cell stimulation. When peripheral blood mononuclear cells (PBMC) were pulsed with li hybrids encoding T cell epitopes of tetanus toxin or acetylcholine receptor, stimulation of T cells was dramatically enhanced compared to stimulation after priming with either the native or recombinant proteins. Site-specific insertion of antigenic sequences into the CLIP region promoted enhanced antigenicity of li hybrids which were shown to be processed intracellularly in a chloroquine-sensitive compartment. Naturally processed T helper epitopes were visualized directly on the surface of PBMC and identified as analogs of CLIP associated with MHC class II molecules. This novel li vector provides a flexible and efficient system for the delivery of defined peptide epitopes to T cells which might be useful in the development of specific vaccines and in the study of intracellular processing.
authors.affiliation: Department of Neurology, University of Tübingen, Germany. malcher@icrf.icnet.uk
authors.forename: G
authors.initials: G
authors.lastname: Malcherek
authors.forename: C
authors.initials: C
authors.lastname: Wirblich
authors.forename: N
authors.initials: N
authors.lastname: Willcox
authors.forename: H G
authors.initials: HG
authors.lastname: Rammensee
authors.forename: J
authors.initials: J
authors.lastname: Trowsdale
authors.forename: A
authors.initials: A
authors.lastname: Melms
mesh_terms: D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000235:genetics*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005822:Genetic Vectors / Q000138:chemical synthesis / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007424:Intracellular Fluid / Q000378:metabolism; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000235:genetics; D015202:Protein Engineering; D011950:Receptors, Cholinergic / Q000235:genetics / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013744:Tetanus Toxin / Q000235:genetics / Q000276:immunology
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D015804:HLA-DR4 Antigen; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D011950:Receptors, Cholinergic; D011993:Recombinant Fusion Proteins; D013744:Tetanus Toxin; C045084:invariant chain