We invite you to join our seminar at UCSF Mission Bay campus with Paul Norman from University of Colorado Anschutz.
Abstract:
Natural variation of human innate immune cell receptors
Paul Norman, PhD
Professor, Department of Biomedical Informatics, University of Colorado Anschutz
Recognition of peptide-HLA class I complex by natural killer cell receptors across human populations.
The Norman lab investigates how the human MHC (includes HLA lass I and II) and KIR genomic regions determine the outcome of infectious and immune-mediated diseases. Characterized by extreme sequence and structural diversity, they are amongst the most complex, and medically important, regions of the human genome. Our major focus is studying the interaction and co-evolution of HLA with KIR, which are receptors that modulate activity of Natural Killer (NK) cells and some T cells. There are four inhibitory KIR and four activating KIR that interact with HLA class I. This interaction is defined within the HLA class I molecules by epitopes that overlap with the TCR binding site. Accordingly, the activating KIR exhibit sensitivity for peptides presented by HLA class I, favouring those peptides derived from certain pathogens. Through studying both large urban and smaller indigenous populations worldwide we can follow how the KIR/HLA interactions have evolved. We can identify single amino acid substitutions unique to certain populations that determine binding specificity of a given KIR. We identified a KIR allele, having a divergent mutation in the HLA binding site, that was acquired from archaic humans and is now widespread across Oceania. In collaboration with multiple groups from Australia and Papua New Guinea, we investigate the impact of peptide specificity of this inhibitory KIR in determining differential immune responses across individuals. Another highly polymorphic inhibitory receptor is KIR3DL3 that we show is expressed by tissue-resident gut T cells and is upregulated in disease tissue. KIR3DL3 competes with activating CD28H for binding to a B7 family member expressed by epithelial cells. We identify both parallels and distinctions to the established CTLA4/CD28/B7 axis of immune cell modulation.
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