How do cells obey the laws of Chemistry ?
Our research focuses on fundamental Immune recognition mechanisms, along three principal research directions:
The mechanism of Immune antigen repertoire selection
During infection and cancer, class I major histocompatibility complex (MHC-I) molecules selectively capture optimal peptides from a large pool of targets with different sequences, lengths, and affinities for the peptide-binding groove. The peptide loading process is assisted by molecular chaperones, which can accomplish the remarkable feat of selecting sparse peptides under non-equilibrium conditions, via a poorly understood mechanism.
Using NMR, we have recently provided a high-resolution picture of peptide binding to the TAPBPR/MHC-I complex under physiologically relevant conditions. We find that, instead of directly competing with TAPBPR structural elements, incoming peptides allosterically induce TAPBPR dissociation from the complex though specific dynamics changes at both ends of the MHC-I. These results provide new insights into how molecular chaperones “edit” peptide antigens to select a repertoire of kinetically stable, properly conformed pMHC-I molecules which ensures their trafficking and display on the cell surface.
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The triggering of T Cell Signaling
The T cell receptor (TCR) complex is the main signaling hub that controls cell-mediated immune responses. Cytotoxic T cell signaling is triggered through the engagement of pMHC-I molecules on antigen-presenting cells by TCRs on T cells. The signal is relayed from the TCR/pMHC-I interface through interactions with co-receptors to the cytoplasmic side of the T cell. Our aim is to elucidate how subtle changes in protein-protein interactions within the complex result in T cell activation. We have recently identified a conserved allosteric site at the interface of the TCR alpha/beta constant regions, which undergoes a conformational change upon pMHC-I binding, critical for signaling via the CD3 co-receptor. Follow up studies with different pMHC-I ligands will provide additional clues on how the structural and dynamic features of pMHC-I recondition by the TCR can be integrated at multiple levels to trigger a spectrum of responses by the T cell.
The Molecular Basis of Viral Immune Evasion
Viral immunoevasins are key molecules employed by viruses to subvert the host immune response during infection. Understanding the molecular basis of their functions is key for explaining how viruses have adapted to specifically infect selected hosts and for the design of new vaccines and other antiviral therapies. Mouse cytomegalovirus (MCMV) has a set of such proteins that specifically interfere with major histocompatibility complex class I (MHC-I) antigen presentation to CD8+ T cells and natural killer (NK) cells. We have developed a new approach that combines sparse datasets from NMR with advanced computational modeling methods. We have previously applied this approach to elucidate the solution structure of the m04/gp34 Immunoevasin, and are currently extending these methods to determine the structures of MHC/Immunoevasin complexes.