Invariant chains with the class II binding site replaced by a sequence from influenza virus matrix protein constrain low-affinity sequences to MHC II presentation. Int Immunol 2000 Nov;12(11):1561-8
Date
11/04/2000Pubmed ID
11058576DOI
10.1093/intimm/12.11.1561Scopus ID
2-s2.0-0033739254 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
Presentation of antigenic peptides by MHC II molecules is required to initiate CD4 T(h) cell responses. Some peptides, however, because of low affinity for MHC II, are not efficiently presented. A segment of the MHC II chaperon molecule, invariant chain (Ii), is known to bind early in biosynthesis with low affinity to the peptide binding groove. Here we have exploited the properties of Ii to manipulate the MHC II-loading pathway and to present low-affinity sequences. We used a deletion mutant of Ii where the promiscuous binding site to MHC II, which is adjacent to the groove binding segment, was deleted. A recombinant Ii (rIi) chimera, derived from this construct, was made in which the class II binding segment was exchanged for wild-type or single amino acid substitution variants of an HLA-DR1-restricted sequence from influenza matrix protein (MAT), which leads to MHC II allotype-specific binding. This rIi was expressed in antigen-presenting cells (APC) and introduced the MAT sequence into the MHC II-processing pathway. As expected, rIiMAT elicited antigen-specific, DR1-restricted T cell cytokine production and proliferation. Significantly, rIiMAT, that binds the HLA-DR4 allele with low affinity, elicited DR4-restricted IL-2 production but not proliferation. In contrast, exogenously provided MAT peptide failed to elicit any responses from DR4-restricted T cells. Compatible results were obtained with a single amino acid substitution variant (MAT(T)), which binds with high affinity to DR4 but low affinity to DR1. We conclude that loading of MHC II with antigenic peptides from endogenously synthesized rIi chimeras allows presentation of low-affinity sequences that cannot be presented if provided exogenously as peptides. Ii fusion proteins containing low-affinity antigenic sequences might be useful for vaccination with tumor antigens to overcome deficiencies in antigen presentation.
Author List
Carstens C, Newman DK, Bohlen H, König A, Koch NAuthors
Debra K. Newman PhD Investigator in the Blood Research Institute department at BloodCenter of WisconsinDebra K. Newman PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AdultAlleles
Amino Acid Sequence
Animals
Antigen Presentation
Antigens, Differentiation, B-Lymphocyte
Binding Sites
Genetic Vectors
HLA-DR Antigens
Histocompatibility Antigens Class II
Histocompatibility Testing
Humans
Influenza A virus
Interleukin-2
Mice
Molecular Sequence Data
Peptide Fragments
Recombinant Fusion Proteins
T-Lymphocytes
Tumor Cells, Cultured
Viral Matrix Proteins