Mechanistic Molecular Immunology Lab

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We are currently accepting students through the Immunology, Biochemistry and Molecular Biophysics, and Pharmacology Graduate Groups. Please visit careers.chop.edu for more information.

The Mechanistic Molecular Immunology Lab investigates the processes that enable adaptive immune responses against infectious diseases and cancer. Our lab's principal efforts focus on mechanistic, structural and functional studies of protein complexes, with emphasis on the development of an iterative experimental / computational approach. To gain an atomic-detail description of these processes and to characterize novel therapeutic targets, we integrate cutting-edge structural biology methods from Nuclear Magnetic Resonance Spectroscopy, complementary biophysical and biochemical techniques, computational modeling and functional immunoassays. Our efforts are done in close collaboration with several groups within the vibrant immunology and immuno-oncology communities at Children's Hospital of Philadelphia and the University of Pennsylvania.

The class-I and class-II proteins of the Major Histocompatibility Complex play an essential role in immune surveillance, by displaying epitopic peptides derived from the processing of aberrant proteins on the cell surface, where they can be recognized through interactions with specialized receptors on T cells and Natural Killer cells. In recent work, our team found that the dynamic plasticity of MHC-I proteins, occurring over a range of timescales from microseconds to milliseconds, plays an essential role in their peptide selector function though the sampling of minor, “excited-state” conformations. Our detailed biophysical characterization of the molecular chaperone TAPBPR provided us with a high-resolution view of peptide exchange on MHC-I proteins and led to the development a high-throughput methodology for generating barcoded MHC tetramer libraries encompassing hundreds of unique antigen specificities.

Our platform can be combined with single cell transcriptomics to identify and characterize tumor-specific receptors present in the polyclonal T cell repertoires of cancer patients. This information is currently leveraged for the development of more targeted cancer therapeutics, by exploiting both naturally occurring and engineered receptor specificities against recurrent, “public” antigens displayed on classical and non-polymorphic MHC-I alleles.

Project Highlights

  • MHC-I structural dynamics and immune repertoire selection
  • Editing of peptide antigens by molecular chaperones
  • Structural basis of immunodominance in the context of SARS-CoV-2 infection
  • Pleiotropic cytokine dynamics & function
  • Mapping polyclonal TCR repertoires specificities for tumor antigens
Leader

Nikolaos G. Sgourakis, PhD

Principal Investigator
Dr. Sgourakis’ research focuses on understanding the intricate molecular mechanisms that determine the vast repertoire of peptide antigens displayed by the proteins of the Major Histocompatibility Complex for immune surveillance by T cells and Natural Killer cells.