Researchers at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania unlocked important new insights in how the immune system selects the right signals to alert T cells, a vital step in the prevention and treatment of serious illness. The findings were published this week in the journal Proceedings of the National Academy of Sciences (PNAS).
In recent years, researchers have acquired extensive knowledge around adaptive immunity, the body’s defense system that learns to recognize and fight off threats and empower the immune system to respond faster and more effectively. Class 1 major histocompatibility complex (MHC-I) proteins are essential for adaptive immunity because they alert immune cells about harmful invaders in the body. Many of these key signals are carried out by peptides, or small pieces of proteins that perform many essential functions in the body. However, until now, antigen proofreading, the process of selecting the right peptides against a background of millions of possible “decoys” continuously generated in cells, was unclear due to its fleeting and complex nature.
“Our fundamental findings deepen the understanding of how the selection of T cell antigen repertoires works, and open the door to significant medical advancements,” said Nikolaos G. Sgourakis, PhD, a senior study author and Associate Professor in the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia. “We envision these insights leading to new vaccine technologies and adjuvants for improving treatment of cancer, autoimmunity, and infectious diseases.”
In this study, led by Yi Sun, PhD, a graduate student in the Sgourakis lab, researchers focused on the chaperone protein TAPBPR, that plays an important role in assisting MHC-I proteins to select the best peptides, ensuring that only the most effective antigens are displayed to T cells. Researchers used cutting-edge structural biology tools, Nuclear Magnetic Resonance (NMR) spectroscopy and cryo-electron microscopy, as well as specially engineered versions of TAPBPR and MHC-I proteins, to capture a highly detailed snapshot of the interaction. Using shared CHOP/Penn NMR instrumentation, along with support from the Institute for Structural Biology at Penn led by Vera Moiseenkova-Bell, PhD, a study co-author, researchers observed the structure of the molecules in action.
The researchers discovered how brief interactions with peptides help MHC-I molecules, along with their dedicated chaperones, determine if they are a good match. This proofreading step ensures that only strong, stable peptides are selected for display to T cells. The discovery helps explain how the immune system streamlines its response to threats that could harm the body.
The research team also demonstrated that TAPBPR could efficiently exchange peptides on MHC-I proteins in human cells, and as a system to screen for immunogenic peptides in vitro. They are currently collaborating with John M. Maris, MD, a pediatric oncologist at CHOP, to determine whether this approach can facilitate new ways to treat pediatric tumors, such as neuroblastoma.
This research was supported in part by NIH grants (R01AI143997, R35GM125034), Penn Medicine (Q:41036976, R35GM144120), The Children’s Hospital of Philadelphia Cell (977, 978) and the Gene Therapy Collaborative.
Sun et al. “CryoEM structure of an MHC-I/TAPBPR peptide-bound intermediate reveals the mechanism of antigen proofreading.” Online January 9, 2025. DOI: 10.1073/pnas.2416992122.
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Researchers at Children’s Hospital of Philadelphia (CHOP) and the Perelman School of Medicine at the University of Pennsylvania unlocked important new insights in how the immune system selects the right signals to alert T cells, a vital step in the prevention and treatment of serious illness. The findings were published this week in the journal Proceedings of the National Academy of Sciences (PNAS).
In recent years, researchers have acquired extensive knowledge around adaptive immunity, the body’s defense system that learns to recognize and fight off threats and empower the immune system to respond faster and more effectively. Class 1 major histocompatibility complex (MHC-I) proteins are essential for adaptive immunity because they alert immune cells about harmful invaders in the body. Many of these key signals are carried out by peptides, or small pieces of proteins that perform many essential functions in the body. However, until now, antigen proofreading, the process of selecting the right peptides against a background of millions of possible “decoys” continuously generated in cells, was unclear due to its fleeting and complex nature.
“Our fundamental findings deepen the understanding of how the selection of T cell antigen repertoires works, and open the door to significant medical advancements,” said Nikolaos G. Sgourakis, PhD, a senior study author and Associate Professor in the Center for Computational and Genomic Medicine at Children’s Hospital of Philadelphia. “We envision these insights leading to new vaccine technologies and adjuvants for improving treatment of cancer, autoimmunity, and infectious diseases.”
In this study, led by Yi Sun, PhD, a graduate student in the Sgourakis lab, researchers focused on the chaperone protein TAPBPR, that plays an important role in assisting MHC-I proteins to select the best peptides, ensuring that only the most effective antigens are displayed to T cells. Researchers used cutting-edge structural biology tools, Nuclear Magnetic Resonance (NMR) spectroscopy and cryo-electron microscopy, as well as specially engineered versions of TAPBPR and MHC-I proteins, to capture a highly detailed snapshot of the interaction. Using shared CHOP/Penn NMR instrumentation, along with support from the Institute for Structural Biology at Penn led by Vera Moiseenkova-Bell, PhD, a study co-author, researchers observed the structure of the molecules in action.
The researchers discovered how brief interactions with peptides help MHC-I molecules, along with their dedicated chaperones, determine if they are a good match. This proofreading step ensures that only strong, stable peptides are selected for display to T cells. The discovery helps explain how the immune system streamlines its response to threats that could harm the body.
The research team also demonstrated that TAPBPR could efficiently exchange peptides on MHC-I proteins in human cells, and as a system to screen for immunogenic peptides in vitro. They are currently collaborating with John M. Maris, MD, a pediatric oncologist at CHOP, to determine whether this approach can facilitate new ways to treat pediatric tumors, such as neuroblastoma.
This research was supported in part by NIH grants (R01AI143997, R35GM125034), Penn Medicine (Q:41036976, R35GM144120), The Children’s Hospital of Philadelphia Cell (977, 978) and the Gene Therapy Collaborative.
Sun et al. “CryoEM structure of an MHC-I/TAPBPR peptide-bound intermediate reveals the mechanism of antigen proofreading.” Online January 9, 2025. DOI: 10.1073/pnas.2416992122.
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