The polymorphic nature and instability of class I major histocompatibility complex (MHC-I) molecules make using them in therapeutics a challenge. But researchers from the Children’s Hospital of Philadelphia (CHOP) may have solved this problem by engineering stable, universal MHC-I molecules that can be produced rapidly at scale. Recently published in the Proceedings of the National Academy of Sciences, the universal MHC-I molecules could accelerate the development of vaccines and immunotherapies for a variety of conditions.
Creating stable, recombinant, and universal MHC-I molecules
Classic MHC-I molecules consist of three major parts:
a peptide antigen consisting of 8–15 amino acids,
a light chain that is conserved across all MHC-I molecules, and
a highly polymorphic heavy chain.
The researchers tethered the variable heavy chains to the light chains, as the latter stabilized the MHC-I molecules, through an engineered disulfide bond, creating “open” MHC-I molecules.
To ensure the open MHC-I molecules were universal and could bind to peptides of interest on demand, the researchers modified the peptide-binding groove, which contains polymorphic residues governed by HLA types. HLA or human leukocyte antigen, is the MHC system in humans that contains the most polymorphic cluster of genes that have evolved to identify and process a wide range of antigen peptides. Each HLA “allotype” binds to a specific type of antigens, triggers a specific antigen-presenting cascade, and brings about a suitable immune response.
The researchers then refolded open MHC-I molecules with synthetic peptides prepared in vitro to achieve fully functioning, recombinant peptide-loaded MHC-I (pMHC-I) molecules.
Validating the stability and function of pMHC-I molecules
Using nuclear magnetic resonance (NMR), the team showed that the open MHC-I molecules have enhanced stability when loaded with peptides—even those of low to moderate affinity.
The researchers also demonstrated that the pMHC-I molecules promote peptide exchange across multiple HLA allotypes.
“These new molecules could be a versatile tool for screening antigenic epitopes, enabling the detection of low-frequency receptors and engineered antibodies for the development of targeted therapies,” said senior author Nikolaos G. Sgourakis, PhD, associate professor at the Center for Computational and Genomic Medicine, CHOP, in a recent press release.