TY  - JOUR
AU  - Günther, Matthias
AU  - Sticht, Jana
AU  - Freund, Christian
AU  - Höfer, Thomas
TI  - Antigen presentation by MHC-II is shaped by competitive and cooperative allosteric mechanisms of peptide exchange.
JO  - Structure
VL  - 33
IS  - 2
SN  - 0969-2126
CY  - Cambridge, Mass.
PB  - Cell Press
M1  - DKFZ-2024-02761
SP  - 389-400.e13
PY  - 2025
N1  - #EA:B086#LA:B086# / 2025 Feb 6;33(2):389-400.e13
AB  - Major histocompatibility complex class II (MHC-II) presents antigens to T helper cells. The spectrum of presented peptides is regulated by the exchange catalyst human leukocyte antigen DM (HLA-DM), which dissociates peptide-MHC-II complexes in the endosome. How susceptible a peptide is to HLA-DM is mechanistically not understood. Here, we present a data-driven mathematical model for the conformational landscape of MHC-II that explains the wide range of measured HLA-DM susceptibilities and predicts why some peptides are largely HLA-DM-resistant. We find that the conformational plasticity of MHC-II mediates both allosteric competition and cooperation between peptide and HLA-DM. Competition causes HLA-DM susceptibility to be proportional to the intrinsic peptide off-rate. Remarkably, diverse MHC-II allotypes with conserved HLA-DM interactions show a universal linear susceptibility function. However, HLA-DM-resistant peptides deviate from this susceptibility function; we predict resistance to be caused by fast peptide association with MHC-II. Thus, our study provides quantitative insight into peptide and MHC-II allotype parameters that shape class-II antigen presentation.
KW  - HLA-DM (Other)
KW  - HLA-DM susceptibility (Other)
KW  - MHC class-II (Other)
KW  - antigen presentation (Other)
KW  - immunopeptidome prediction (Other)
KW  - mathematical model (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39708815
DO  - DOI:10.1016/j.str.2024.11.014
UR  - https://inrepo02.dkfz.de/record/296018
ER  -