University of Leicester
Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.pdf (2.47 MB)
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Expression levels of MHC class I molecules are inversely correlated with promiscuity of peptide binding.

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journal contribution
posted on 2019-10-24, 10:12 authored by P Chappell, EK Meziane, M Harrison, Ł Magiera, C Hermann, L Mears, AG Wrobel, C Durant, LL Nielsen, S Buus, N Ternette, W Mwangi, C Butter, V Nair, T Ahyee, R Duggleby, A Madrigal, P Roversi, SM Lea, J Kaufman
Highly polymorphic major histocompatibility complex (MHC) molecules are at the heart of adaptive immune responses, playing crucial roles in many kinds of disease and in vaccination. We report that breadth of peptide presentation and level of cell surface expression of class I molecules are inversely correlated in both chickens and humans. This relationship correlates with protective responses against infectious pathogens including Marek's disease virus leading to lethal tumours in chickens and human immunodeficiency virus infection progressing to AIDS in humans. We propose that differences in peptide binding repertoire define two groups of MHC class I molecules strategically evolved as generalists and specialists for different modes of pathogen resistance. We suggest that differences in cell surface expression level ensure the development of optimal peripheral T cell responses. The inverse relationship of peptide repertoire and expression is evidently a fundamental property of MHC molecules, with ramifications extending beyond immunology and medicine to evolutionary biology and conservation.


Funding Wellcome Trust (Programme grant 089305) El Kahina Meziane Michael Harrison Łukasz Magiera Clemens Hermann Laura Mears Antoni G Wrobel Charlotte Durant Jim Kaufman Biotechnology and Biological Sciences Research Council (BBSRC) (Core Funding to the Pirbright Institute) William Mwangi Colin Butter Venugopal Nair Biotechnology and Biological Sciences Research Council (BBSRC) (PhD studentship) Paul E Chappell Wellcome Trust (Senior Investigator Award) Susan M Lea The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. Acknowledgements We thank many colleagues at the IAH (now rebranded as the Pirbright Institute) for much historical help in processing materials for analysis of MHC-bound peptides, especially Larry Hunt from the Protein Chemistry facility for analysis of eluted peptides by Edman degradation and for provision of synthetic peptides. We thank Diamond Light Source for access to beamlines I02, I03, I04, and I04-1 (mx9306) that contributed to the results presented here. The B14 structural experiments were performed on the ID29 beamline at the European Synchrotron Radiation Facility (ESRF), Grenoble, France. We are grateful to Local Contact at ESRF for providing assistance in using beamline ID29. We also thank Ed Lowe from the Biochemistry Department, Oxford for data collection and members of the Lea lab for crystallography discussions. We thank Steve Marsh from the Anthony Nolan, Tom Pizzari from Oxford Zoology, and Lars Råberg from Lund University for helpful discussions. We thank Gillian Griffiths, Alison Schuldt, Michaela Fakiola, and Mike Ratcliffe for critical reading of the manuscript. The authors declare no conflicts of interest.



Elife, 2015;4:e05345

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/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biology


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Structure factors and atomic coordinates have been deposited with the Protein Data Bank under accession codes 2YEZ (BF2*2101 with TNPESKVFYL), 4D0B (BF2*2101 with TAGQEDYDRL), 4D0C (BF2*2101 with TAGQSNYDRL), 4CVZ (BF2*2101 with YELDEKFDRL), 4CVX (BF2*0201 with YPYLGPNTL), 4D0D (BF2*0201 with VIFPAKSL), and 4CW1 (BF2*1401 with SWFRKPMTR).