Soluble MHC-peptide complexes containing long rigid linkers abolish CTL-mediated cytotoxicity.

Details

Serval ID
serval:BIB_8E2DE96E14F3
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Soluble MHC-peptide complexes containing long rigid linkers abolish CTL-mediated cytotoxicity.
Journal
Journal of immunology
Author(s)
Angelov G.S., Guillaume P., Cebecauer M., Bosshard G., Dojcinovic D., Baumgaertner P., Luescher I.F.
ISSN
0022-1767
Publication state
Published
Issued date
2006
Peer-reviewed
Oui
Volume
176
Number
6
Pages
3356-3365
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Soluble MHC-peptide (pMHC) complexes induce intracellular calcium mobilization, diverse phosphorylation events, and death of CD8+ CTL, given that they are at least dimeric and co-engage CD8. By testing dimeric, tetrameric, and octameric pMHC complexes containing spacers of different lengths, we show that their ability to activate CTL decreases as the distance between their subunit MHC complexes increases. Remarkably, pMHC complexes containing long rigid polyproline spacers (> or =80 A) inhibit target cell killing by cloned S14 CTL in a dose- and valence-dependent manner. Long octameric pMHC complexes abolished target cell lysis, even very strong lysis, at nanomolar concentrations. By contrast, an altered peptide ligand antagonist was only weakly inhibitory and only at high concentrations. Long D(b)-gp33 complexes strongly and specifically inhibited the D(b)-restricted lymphocytic choriomeningitis virus CTL response in vitro and in vivo. We show that complications related to transfer of peptide from soluble to cell-associated MHC molecules can be circumvented by using covalent pMHC complexes. Long pMHC complexes efficiently inhibited CTL target cell conjugate formation by interfering with TCR-mediated activation of LFA-1. Such reagents provide a new and powerful means to inhibit Ag-specific CTL responses and hence should be useful to blunt autoimmune disorders such as diabetes type I.
Keywords
Animals, Calcium/metabolism, Cell Adhesion, Cell Death, Cells, Cultured, Cross-Linking Reagents/chemistry, Cytotoxicity, Immunologic/immunology, Dimerization, Histocompatibility Antigens/chemistry, Histocompatibility Antigens/immunology, Lymphocyte Function-Associated Antigen-1/metabolism, Mice, Peptide Fragments/chemistry, Peptide Fragments/metabolism, Peptides/chemistry, Protein Binding, Solubility, T-Lymphocytes, Cytotoxic/cytology, T-Lymphocytes, Cytotoxic/immunology
Pubmed
Web of science
Create date
28/01/2008 11:20
Last modification date
20/08/2019 14:52
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