Structural and regulatory diversity shape HLA-C protein expression levels

  • Nat Commun. 2017 Jun 26;8:15924. doi: 10.1038/ncomms15924.
Gurman Kaur  1 ,  Stephanie Gras  2  3 ,  Jesse I Mobbs  2 ,  Julian P Vivian  2  3 ,  Adrian Cortes  4  5 ,  Thomas Barber  4 ,  Subita Balaram Kuttikkatte  1 ,  Lise Torp Jensen  6 ,  Kathrine E Attfield  1 ,  Calliope A Dendrou  4  5 ,  Mary Carrington  7  8 ,  Gil McVean  5  9 ,  Anthony W Purcell  2 ,  Jamie Rossjohn  2  3  10 ,  Lars Fugger  1  4  6
Affiliations
  • 1. MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • 2. Infection and Immunity Program and the Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria 3800, Australia.
  • 3. Australian Research Council Centre of Excellence in Advanced Molecular Imaging, Monash University, Clayton, Victoria 3800, Australia.
  • 4. Oxford Centre for Neuroinflammation, Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.
  • 5. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  • 6. Department of Clinical Medicine, Aarhus University Hospital, 8200N Aarhus, Denmark.
  • 7. Cancer and Inflammation Program, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA.
  • 8. The Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts 02139, USA.
  • 9. Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, University of Oxford, Oxford OX3 7FZ, UK.
  • 10. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
PMID: 28649982 DOI: 10.1038/ncomms15924
Abstract

Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the α1/α2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of Peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression.