Work

Antigen presentation by MHC-II is shaped by competitive and cooperative allosteric mechanisms of peptide exchange

Year: 2024

Type: article

Abstract: 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.

Source: Structure

DOI: 10.1016/j.str.2024.11.014

Authors: Matthias Günther, Jana Sticht, Christian Freund, Thomas Höfer

Institutions: German Cancer Research Center, Freie Universität Berlin

Language: English

Topic: vaccines and immunoinformatics approaches

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

Open Access status: hybrid

Estimated APC paid: $9,350

Funders: Deutsches Krebsforschungszentrum, Deutsche Forschungsgemeinschaft