Cellular Immunology

Scott Burrows Staff
Key Recent Publications
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Lab Head: Associate Professor Scott Burrows

The Cellular Immunology Laboratory was established at the beginning of 2002 by Dr Scott Burrows with a main focus on cytotoxic T lymphocytes (CTL) and factors controlling their primary functions, killing virus-infected cells, foreign transplanted cells and tumour cells. We have several defined projects already available to students as well as flexibility to incorporate additional projects.

Foreign peptide epitopes are present on the surface of virus-infected cells and some tumour cells. These are recognised by the CTLs of the immune system only when bound to cell surface molecules called histocompatibility antigens (HLAs) in humans. These HLAs are a highly polymorphic class of molecules, with each different HLA capable of binding a distinct set of antigenic peptides. Over the last 2 decades Dr Burrows has played a major role in identifying the viral peptides that are recognised in the CTL response to Epstein-Barr virus (EBV), the virus that causes glandular fever (also called infectious mononucleosis) and is associated with various cancers such as nasopharyngeal carcinoma and Hogkin's disease. These viral peptides are now being used in the design of vaccines against this virus.

Cytotoxic cell Although the viral peptides recognised by the CTL response to many different viruses are well defined, it is still not clear why some viral peptides stimulate stronger CTL responses than others. Our recent studies have shown that the shape of the peptide, when bound to the cell surface HLA molecules, can have a major impact on the strength of the CTL response to a viral peptide. We plan to investigate this issue further to try to understand how peptide conformation can influence the immune response. We are also interested in unusually long viral CTL epitopes. It is assumed by most immunologists that the most important viral peptides targeted by the CTL response are of a very limited length from 8-10 amino acids. However, we have recently shown that viral peptides of 11-13 amino acids in length can have a major role as target epitopes for the CTL response. Furthermore, in recent months we have mapped the longest known epitope for CTL recognition, an extraordinarily large peptide from EBV with a minimal length of 16 amino acids. Our future studies will investigate how these long peptides are presented by HLA molecules and are recognised by the CTL response. We will also investigate why such unusually long viral peptides are sometimes recognised by CTLs in preference to overlapping viral peptides of more conventional length.

The critical molecule on the surface of CTLs that is involved in specific recognition of viral peptides is the T cell receptor (TCR). To accommodate the huge variety of viral peptides presented by infected cells, millions of different TCR molecules are expressed by CTLs to ensure an appropriate TCR is available for binding to most viral peptides. Interestingly, some viral peptides are recognised by a large variety of TCR molecules while others are targeted by very few and we are investigating the factors that influence this unexplained phenomonon.

Although the primary role of CTLs is to kill virus-infected cells and tumour cells, they can have a negative impact on human health. In transplant patients, CTLs play a major role in the rejection response, and immunosuppressive therapy is routinely administered to dampen the immune system. This nonspecific immunosuppression is far from ideal, leading to many unwanted side effects such as increased cancer rates. Recent data from this laboratory has suggested that it may be possible to suppress, quite specifically, only those CTLs responsible for the rejection response in transplant patients. This project follows from an observation made by Dr Burrows and colleagues many years ago that the CTLs responding to foreign HLAs are sometimes quite restricted in their diversity, with one clonotype dominating some responses. We have now shown that it is possible to specifically inhibit such dominant T cell clonotypes with the potential to attack foreign transplanted tissue by exploiting a phenomenon called altered peptide ligand antagonism. Thus, synthetic peptides with minor modifications to the target peptide of CTLs that have the capacity to kill foreign cells were shown to inhibit these CTLs. This study has now raised the prespect that such TCR antagonists could be exploited within the clinical arena to specifically modulate allograft rejection.

Staff

Labhead:	Assoc Prof Scott Burrows
Senior Research Officer:	Dr Sharon Silins
Research Assistants:	Melissa Bell Jacqueline Burrows
PhD Student:	Rebekah Brennan

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Key Publications

Tynan, F.E., Reid, H.H., Kjer-Nielsen, L., Miles, J.J., Wilce, M.C.J., Kostenko, L., Borg, N.A., Williamson, N.A., Beddoe, T., Purcell, A.W., Burrows, S.R., McCluskey, J., and Rossjohn, J. 2007. A T cell receptor flattens a bulged antigenic peptide presented by a major histocompatibility complex class I molecule. Nature Immunol. 8:268-276. [pubmed abstract]

Brennan, R.M., Miles, J.J., Silins, S.L., Bell, M.J., Burrows, J.M., and Burrows, S.R. 2007. Predictable aß T-cell receptor selection towards an HLA-B*3501-restricted, human cytomegalovirus epitope. J. Virol. 81:7269-7273. [pubmed abstract]

Burrows, J.M., Wynn, K.K., Tynan, F.E., Archbold, J., Miles, J.J., Bell, M.J., Brennan, R.M., Walker, S., McCluskey, J., Rossjohn, J., Khanna, R., and Burrows, S.R. 2007. The impact of HLA micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV. Eur. J. Immunol. 37:946-953. [pubmed abstract]

Burrows, J.M., Bell, M.J., Brennan, R.M., Miles, J.J., Khanna, R., and Burrows, S.R. 2008. Preferential binding of unusually long peptides to MHC class I and its influence on the selection of target peptides for T cell recognition. Mol. Immunol. 45:1818-1824. [pubmed abstract]

Kjer-Nielsen, L., Clements, C.S., Purcell, A.W., Brooks, A.G., Whisstock, J.C., Burrows, S.R., McCluskey, J. and Rossjohn, J. 2003. A structural basis for the selection of dominant aß T cell receptors in antiviral immunity. Immunity 18:53-64. [pubmed abstract]

Burrows, S.R., Elkington, R.A., Miles, J.J., Green, K.J., Walker, S., Haryana, S.M., Moss, D.J., Dunckley, H., Burrows, J.M. and Khanna R. 2003. Promiscuous CTL recognition of viral epitopes on multiple human leukocyte antigens: biological validation of the proposed HLA A24 supertype. J. Immunol. 171:1407-1412. [pubmed abstract]

Green, K.J., Miles, J.J., Tellam, J., van Zuylen, W.J.M.,Connolly, G. and Burrows, S.R. 2004. Potent T cell response to a class-I-binding 13-mer viral epitope and the influence of HLA micropolymorphism in controlling epitope length. Eur. J. Immunol. 34:2510-2519. [pubmed abstract]

Tellam, J., Connolly, G., Green, K.J., Miles, J.J., Moss, D.J., Burrows, S.R. and Khanna, R. 2004. Endogenous presentation of CD8+ T cell epitopes from Epstein-Barr virus encoded nuclear antigen 1. J. Exp. Med. 199: 1421-1431.[pubmed abstract]

Borg, N.A., Ely, L.K., Beddoe, T., Macdonald, W.A., Reid, H.H., Clements, C.S., Purcell, A.W., Kjer-Nielsen, L., Miles, J.J., Burrows, S.R., McCluskey, J. and Rossjohn, J. 2005. The CDR3 regions of an immunodominant T cell receptor dictate the "energetic landscape" of peptide-MHC recognition. Nature Immunol. 6:171-180. [pubmed abstract]

Ely, L.K., Green, K.J., Beddoe, T., Clements, C.S., Miles, J.J., Bottomley, S.P., Zernich, D., Kjer-Nielsen, L., Purcell, A.W., McCluskey, J., Rossjohn, J. and Burrows, S.R. 2005. Antagonism of antiviral and allogeneic activity of a human public CTL clonotype by a single altered peptide ligand: implications for allograft rejection. J. Immunol. 174:5593-5601. [pubmed abstract]

Tynan, F.E., Borg, N.A., Miles, J.J., Beddoe, T., El-Hassen, D., Silins, S.L., van Zuylen, W.J.M., Purcell, A.W., Kjer-Nielsen, L., McCluskey, J., Burrows, S.R. and Rossjohn, J. 2005. High resolution structures of highly bulged viral epitopes bound to the major histocompatibility class I : implications for T-cell receptor engagement and T-cell immunodominance. J. Biol. Chem. 280:23900-23909. [pubmed abstract]

Miles, J.J., Elhassen, D., Borg, N.A., Silins, S.L., Tynan, F.E., Burrows, J.M., Purcell, A.W., Kjer-Nielsen, L., Rossjohn, J., Burrows, S.R. and McCluskey, J. 2005. CTL recognition of a bulged viral peptide involves biased TCR selection. J. Immunol. 175:3826-3834. [pubmed abstract]

Tynan, F.E., Elhassen, D., Purcell, A.W., Burrows, J.M., Borg, N.A., Miles, J.J., Williamson, N.A., Green, K.J., Tellam, J., Kjer-Nielsen, L., McCluskey, J., Rossjohn J. and Burrows, S.R. 2005. The immunogenicity of a viral cytotoxic T cell epitope is controlled by its MHC-bound conformation. J. Exp. Med. 202:1249-1260. [pubmed abstract]

Tynan, F.E., Burrows, S.R., Buckle, A.M., Clements, C.S., Borg, N.A., Miles, J.J., Beddoe, T., Whisstock, J.C., Wilce, M.C., Silins, S.L., Burrows, J.M., Kjer-Nielsen, L., Kostenko, L., Purcell, A.W., McCluskey, J. and Rossjohn, J. 2005. T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide. Nature Immumol. 6:1114-1122. [pubmed abstract]

Miles, J.J., Silins, S.L., Brooks, A.G., Davis, J.E., Misko, I. and Burrows, S.R. 2005. T cell grit: large clonal expansions of virus-specific CD8+ T cells can dominate in the peripheral circulation for at least 18 years. Blood 106:4412-4413. [pubmed abstract]

Burrows, S.R., Rossjohn, J. and McCluskey, J. 2006. Have we cut ourselves too short in mapping CTL epitopes? Trends Immunol. 27: 11-16. [pubmed abstract]

Miles, J.J., Borg, N.A., Brennan, R.M., Tynan, F.E., Kjer-Nielsen, L., Silins, S.L., Bell, M.J., Burrows, J.M., McCluskey, J., Rossjohn, J., and Burrows, S.R. 2006. TCRa genes direct MHC-restriction in the potent human T cell response to a class-I-bound viral epitope. J. Immunol. 177:6804-6814. [pubmed abstract]