What is the Role of MHC-I Proteins in Immune Surveillance?

Using cryogenic electron microscopy (CryoEM), CHOP researchers captured the first clear picture of an MHC-I molecule as it screens for peptides. Image and video credit: Yi Sun, PhD, and Sagar Gupta

The Findings

Researchers at Children's Hospital of Philadelphia and the University of Pennsylvania generated the first clear picture of a critical immune system process. Using cryogenic electron microscopy (CryoEM) and advanced analytical techniques, they captured a structural snapshot of a polymorphic I major histocompatibility complex (MHC-I) molecule caught in the act of scrutinizing a potential peptide antigen under the guidance of a molecular machine, called the TAPBPR "chaperone."

The CryoEM structure shows how, with the assistance of the chaperone, the MHC-I captures and rapidly screens peptides within a few thousandths of a second. Using a complex process that involves changes in protein dynamics, the MHC-I then decides which peptides are going to continue and which are going to be ejected.

Why It Matters

MHC-I molecules are proteins found on the surface of cells that play a key role in adaptive immunity. Peptides are short chains of amino acids, derived from all intracellular proteins, that serve as "barcodes" for immune surveillance. Against a vast background of possible "decoys," MHC-I proteins select peptide fragments, or antigens, to display on the cell surface. These antigens signal the immune system to destroy cells that are infected or cancerous.

The question of how peptides interact with MHC molecules to mediate this selection process has eluded structural biologists for the past decade. By revealing the underpinnings of this molecular process, this study opens the door to significant medical advancements, including informing and advancing treatments for cancer and infectious diseases. The findings could play a role in the quicker development of peptide-based, personalized vaccines.

Who Conducted the Study

Nikolaos G. Sgourakis, PhD, an Associate Professor in the Center for Computational and Genomic Medicine, led the study, alongside Vera Moiseenkova-Bell, PhD, a Professor in the Department of Systems Pharmacology and Translational Therapeutics at Penn's Perelman School of Medicine. Yi Sun, PhD, a former doctoral student in the Sgourakis Lab, was the study's lead author.

How They Did It

Through a series of cutting-edge protein engineering tools and methodological advances developed in Dr. Sgourakis' Mechanistic Molecular Immunology Lab, the researchers developed an artificial, high-fidelity chaperone that magnified its natural-occurring functions and allowed the team to capture and visualize its effects.

Quick Thoughts

"From a pool of millions of peptides, a few thousand are going to be selected and displayed on the cell surface by each polymorphic MHC-I protein," Dr. Sgourakis said. "Now that we can visualize exactly how this selection process happens, we can predict what makes a good antigen. That's such an important question in immunology because it ultimately helps us design better vaccines, understand relevant therapeutic targets, and engineer this system to influence our cells."

What's Next

The researchers are collaborating with John Maris, MD, the Giulio D'Angio Chair in Neuroblastoma Research at CHOP, to screen for immunogenic peptides that could enhance the antigen response in tumors that are unlikely to respond to typical immunotherapy. This approach could treat pediatric cancers such as high-risk neuroblastoma.

Where the Study Was Published

The findings appeared in the Proceedings of the National Academy of Sciences. Read more in a CHOP press release.

CryoEM Structure of an MHC-I/TAPBPR Peptide Bound Intermediate. Access the video transcript