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

The Journal of Immunology : Official Journal of the American Association of Immunologists
Georgi S AngelovImmanuel F Luescher

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 r...Continue Reading

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Citations

Dec 18, 2008·International Immunology·Georgi S AngelovImmanuel F Luescher
Aug 10, 2011·Proceedings of the National Academy of Sciences of the United States of America·Dibyendu SamantaSteven C Almo
Nov 2, 2016·Current Protocols in Immunology·John D Altman, Mark M Davis
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Jun 14, 2012·Clinical & Developmental Immunology·Greg S Gojanovich, Paul R Hess
Jun 27, 2008·The Journal of Biological Chemistry·Jean-Manuel SeguraImmanuel F Luescher
Sep 5, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Philippe GuillaumeImmanuel F Luescher
Dec 5, 2015·Frontiers in Immunology·Michael HebeisenNathalie Rufer
Dec 26, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Valérie CessonAlena Donda
Sep 30, 2021·Scientific Reports·Ronald D SeidelRodolfo J Chaparro

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