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Neil Barclay's
Molecular Immunology Group

 


 

 

 

fOx.crest

 

A Neil Barclay

EP Abraham Professor of Chemical Pathology
Sir William Dunn School of Pathology
University of Oxford
Oxford OX1 3RE, UK
Phone: (01865) 275598

 

 

 

 

 

 

 

 

Outline of
Research

 

Several hundred different proteins at the surface of leukocytes have been recognised and are presumed to be important in the function of these cell types namely the immune response. Leukocytes migrate between tissues until they are stimulated in a specific manner. Thus the cell surfaces of these cells are likely to be involved in specifying the migration and interactions of these cells, receptors for cytokines that control these responses and in specific antigen recognition. In addition the cell surface allows highly focused fine control of immune cells through interactions between proteins on opposing cells. These proteins are diverging rapidly under pathogen pressure. The principle focus of this molecular immunology group is to characterise these interactions at a molecular level and work out their functions. There are two different approaches. One is to take a function and work out the molecular mechanisms involved and the second is to look at the molecules at the surface on cells and ask what functions they do. It is the latter approach that is the main focus of this programme. Many of the interactions of the extracellular regions of membrane proteins are of low affinity (van der Merwe and Barclay 1994) and methods of detecting these have been developed by Marion H. Brown (Brown et al 1995, 1998).  A variety of different proteins are being studied especially those with Ig like domains e.g. CD200, CD47, SIRPs (CD172) and those with scavenger receptor cysteine rich domains (e.g. CD5, CD6 see Marion H. Brown ). In addition some interactions of the membrane (Kirk et al 2000) and cytoplasmic regions are being studied (Hutchings et al 2003). Cell surface proteins are good targets for immunotherapy and proteins we have characterised such as CD200 and CD47 have recently been taken up by the cancer community and are being evaluated as a possible therapeutics..

There are three main foci, one to determine the structure of different proteins at the surface of lymphocyte membranes and the other to identify those membrane proteins that may be useful therapeutic targets and in particular for autoimmune diseases. Thus the aim is to understand the regulation of the immune system through the lymphocyte cell surface at a molecular level. A particular focus is the structural basis of paired receptors with comprehensive structures of the CD200R and SIRP receptor families leading to new theories for their function and evolution (Barclay and Hatherley 2008).

Secondly to use the availability of recombinant proteins and monoclonal antibodies produced in these studies provides reagents with the potential to manipulate the immune response e.g. to switch off aberrant responses such as in autoimmune diseases. These projects help in understanding the role of the proteins and also are possible therapeutic targets. Other groups are evaluating CD200 and CD47 as targets for antibody treatment of leukaemia.

Thirdly a new research programme is being developed to understand the role of labile disulfide bonds in membrane proteins of leukocytes using highly sensitive mass spectrometry methods. These labile disulfides bonds are present in many different types of membrane protein and are often modified during inflammation and have significant effects on the regulation of leukocyte activity (Metcalfe et al 2011, 2012).

I am not recruiting further staff as the laboratory will close at the end of 2015. Marion H. Brown is continuing on the CD5/6 and SLAM families.

 

 

 

 

 

 

 


Recent Group Publications

 

 

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Kwong LS, Brown MH, Barclay AN, Hatherley D. 2014. Signal-regulatory protein alpha from the NOD mouse binds human CD47 with an exceptionally high affinity-- implications for engraftment of human cells. Immunology; 143:61-7.

 

Hatherley D, Lea SM, Johnson S, Barclay AN. 2014. Polymorphisms in the human inhibitory signal-regulatory protein alpha do not affect binding to its ligand CD47. J Biol Chem; 289:10024-8.

 

Barclay AN, Van den Berg TK. 2014. The interaction between signal regulatory protein alpha (SIRPalpha) and CD47: structure, function, and therapeutic target. Annual Review of Immunology; 32:25-50.

 

Stegmann M, Metcalfe C, Barclay AN. 2013. Immunoregulation through membrane proteins modified by reducing conditions induced by immune reactions. Eur J Immunol 2013; 43:15-21.

 

Nettleship JE, Ren J, Scott DJ, et al. 2013. Crystal structure of signal regulatory protein gamma (SIRPgamma) in complex with an antibody Fab fragment. BMC structural biology; 13:13.

 

Hatherley D, Lea SM, Johnson S, Barclay AN. 2013. Structures of CD200/CD200 receptor family and implications for topology, regulation, and evolution. Structure; 21:820-32.

 

Akkaya M, Barclay AN. 2013. How do pathogens drive the evolution of paired receptors? Eur J Immunol 2013; 43:303-13.

 

Akkaya M, Aknin ML, Akkaya B, Barclay AN. 2013. Dissection of agonistic and blocking effects of CD200 receptor antibodies. PloS One; 8:e63325.

 

Metcalfe, C., Cresswell, P, Barclay, AN 2012. Interleukin-2 signalling is modulated by a labile disulfide bond in the CD132 chain of its receptor

Open Biol January 2012 2:110036; doi:10.1098/rsob.110036

 

 Metcalfe, C., Cresswell, P, Ciaccia, L, Thomas, B, Barclay, AN 2011. Labile disulfide bonds are common at the leucocyte cell surface

 Open Biol November 2011 1:110010; doi:10.1098/rsob.110010.

 

Foster-Cuevas M, Westerholt T, Ahmed M, Brown MH, Barclay AN, Voigt S. 2011. Cytomegalovirus e127 Protein Interacts with the Inhibitory CD200 Receptor

J Virol. 85:6055-9.

 

Mukhopadhyay S, Plüddemann A, Hoe JC, Williams KJ, Varin A, Makepeace K, Aknin ML, Bowdish DM, Smale ST, Barclay AN, Gordon S.  2010 Immune inhibitory ligand CD200 induction by TLRs and NLRs limits macrophage activation to protect the host from meningococcal septicaemia Cell Host Microbe;8:236-47.

 

Jiang, L., and A. N. Barclay. 2010. Identification of Leukocyte Surface Protein Interactions by High-Throughput Screening with Multivalent Reagents Immunology 129:55-61.

 

Akkaya, M., and A. N. Barclay. 2010. Heterogeneity in the CD200R paired receptor family. Immunogenetics 62:15-22.

 

Mihrshahi R, Barclay AN, Brown MH. 2009. Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. J. Immunol. 183: 4879-86

 

Zhang L, Stanford M, Liu J, Barrett C, Jiang L, Barclay AN, McFadden G. 2009. Inhibition of macrophage activation by the myxoma virus M141 protein (vCD200). J Virol.  83: 9602-7

 

Hatherley D, Graham SC, Harlos K, Stuart DI, Barclay AN. 2009. Structure of signal-regulatory protein alpha: a link to antigen receptor evolution. J. Biol. Chem. 284: 26613-9

 

Barclay, A. N. 2009. Signal regulatory protein alpha (SIRPalpha)/CD47 interaction and function. Curr Opin Immunol 21:47-52.

 

Jiang, L., and A. N. Barclay. 2009. New assay to detect low-affinity interactions and characterization of leukocyte receptors for collagen including leukocyte-associated Ig-like receptor-1 (LAIR-1). Eur J Immunol 39:1167-1175.

 

Barclay AN and D Hatherley  (2008) The counterbalance theory for evolution and function of paired receptors Immunity 29, 675-678.

 

Hatherley, D., S. C. Graham, J. Turner, K. Harlos, D. I. Stuart, and A. N. Barclay. 2008. Paired Receptor Specificity Explained by Structures of Signal Regulatory Proteins Alone and Complexed with CD47. Molecular Cell 31:266-277.

 

Snelgrove, R. J., J. Goulding, A. M. Didierlaurent, D. Lyonga, S. Vekaria, L. Edwards, E. Gwyer, J. D. Sedgwick, A. N. Barclay, and T. Hussell. 2008. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nat Immunol 9: 1074-1083.

 

Nettleship, J. E., J. Ren, N. Rahman, N. S. Berrow, D. Hatherley, A. N. Barclay, and R. J. Owens. 2008. A pipeline for the production of antibody fragments for structural studies using transient expression in HEK 293T cells. Protein Expr Purif. 62(1):83-9

 

Adams, J. C., A. A. Bentley, M. Kvansakul, D. Hatherley, and E. Hohenester. 2008. Extracellular matrix retention of thrombospondin 1 is controlled by its conserved C-terminal region. J Cell Sci 121:784-795.

 

Hatherley, D., K. Harlos, D. C. Dunlop, D. I. Stuart, and A. N. Barclay. 2007. The structure of the macrophage signal regulatory protein alpha (SIRPalpha) inhibitory receptor reveals a binding face reminiscent of that used by T cell receptors. J. Biol. Chem. 282:14567-14575.

 

Hassan, N. J., S. J. Simmonds, N. G. Clarkson, S. Hanrahan, M. J. Puklavec, M. Bomb, A. N. Barclay, and M. H. Brown. 2006. CD6 Regulates T-Cell Responses through Activation-Dependent Recruitment of the Positive Regulator SLP-76. Mol. Cell. Biol. 26:6727-6738.

 

Barclay A.N. and Brown M.H. 2006. The SIRP family of receptors and immune regulation. Nat Rev Immunol 6: 457-464.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 


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