Rigid, bivalent CTLA-4 binding to CD80 is required to disrupt the cis CD80/PD-L1 interaction
. 2024 Sep 14;43(9):114768.
doi: 10.1016/j.celrep.2024.114768.
Online ahead of print.
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Cell Rep.
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Abstract
The CTLA-4 and PD-1 checkpoints control immune responses and are key targets in immunotherapy. Both pathways are connected via a cis interaction between CD80 and PD-L1, the ligands for CTLA-4 and PD-1, respectively. This cis interaction prevents PD-1-PD-L1 binding but is reversed by CTLA-4 trans-endocytosis of CD80. However, how CTLA-4 selectively removes CD80, but not PD-L1, is unclear. Here, we show CTLA-4-CD80 interactions are unimpeded by PD-L1 and that CTLA-4 binding with CD80 does not displace PD-L1 per se. Rather, both rigidity and bivalency of CTLA-4 molecules are required to orientate CD80 such that PD-L1 interactions are no longer permissible. Moreover, soluble CTLA-4 released PD-L1 only at specific expression levels of CD80 and PD-L1, whereas CTLA-4 trans-endocytosis released PD-L1 in all conditions. These data show that PD-L1 release from CD80 is driven by orientation and bivalent cross-linking of membrane proteins and that trans-endocytosis of CD80 efficiently promotes PD-L1 availability.
Keywords:
CP: Immunology.
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of interests C.T.O., H.-C.C., C.L., and S.J.D. are full-time employees at and shareholders of AstraZeneca. M.A.R. and L.F. received funding from AstraZeneca in support of this work.
Fonte original PubMed