Medicine

Tim Elliott

BA, PhD

Primary position:
Professor of Experimental Medicine
Other positions:
Associate Dean for Research

Background

The University of Southampton

Professor Tim Elliott left the University of Oxford with a first in Biochemistry in 1983, received a PhD from the University of Southampton in 1986 and completed his postdoctoral training at MIT. He held a lectureship and later a professorship in immunology (Weatherall Institute for Molecular Medicine and Balliol College, University of Oxford) between 1990-2000 before being appointed to the Chair of Experimental Oncology, School of Medicine, University of Southampton. In 2005 he became Director of Research for the School of Medicine. He sits on the Editorial Boards of the Journal of Biological Chemistry, Immunology, Current Molecular Medicine, Medical Hypotheses and Research, Cellular Calcium, Current Chemical Biology; and has held appointments on Scientific Advisory boards at the Wellcome Trust, the Association of International Cancer Research, Leukaemia and Lymphoma Research, and Symphogen. He has published over 100 papers (h-index, 34) in the field of molecular immunology; was visiting lecturer of the Alberta Heritage Foundation for Medical Research, University of Edmonton, Alberta in 1999; and recently held a visiting Professorship at the Netherlands Cancer Institute, Amsterdam.

Professor Elliott was amongst the key group of immunologists who developed studies of antigen presentation at the molecular level during the 1980s, undertaking a series of studies to determine and define the immunostimulatory properties of MHC Class I molecules and elucidating the molecular mechanisms of co-factor assisted peptide loading of MHC Class I in antigen presenting cells: work considered to be the fundamental foundation of much of the recent work on antigen presentation. The work underpins rational T-cell based vaccine design and continues to fuel translational research in Southampton where discoveries in the areas of antigen discovery, T cell regulation and immunodominance are making a significant impact on new and ongoing cancer vaccine trials. His mechanistic studies have always benefitted from an active interface with the physical sciences including collaborations with synthetic and computational chemistry and recently with Microsoft UK to model the Class I antigen processing pathway in collaboration with structural biologists in Southampton.

He has developed a new 4 year integrated PhD programme in Biomedical Science which is now in its fifth year. He led the RAE submissions for the school of medicine, and has taken a leading role in developing the new cross-faculty, interdisciplinary Institute for Life Sciences which he is now Deputy Director of.

Qualifications

BA (Hons) Biochemistry 1st class, University of Oxford (1983)
PhD, Immunology, University of Southampton (1986)

Appointments held

Research Associate, Centre for Cancer Research, Massachussetts Institute of Technology, Cambridge, Massachussetts. 1986-1990

Lecturer and Wellcome Trust Junior Research Fellow in Basic Biomedical Science, Institute of Molecular Medicine and Nuffield Department of Clinical Medicine, University of Oxford. 1990-1994

Senior Lecturer and Wellcome Trust Senior Research Fellow in Basic Biomedical Science, Institute of Molecular Medicine and Nuffield Department of Clinical Medicine, University of Oxford. 1994-2000

Professor of Immunology and Wellcome Trust Senior Research Fellow in Basic Biomedical Science, Institute of Molecular Medicine and Nuffield Department of Clinical Medicine, University of Oxford. 1999

Professor of Experimental Medicine, Faculty of Medicine, University of Southampton. 2000 to present

Currently Associate Dean for Research

Professor Tim Elliott's photo

Publications

The University of Southampton's electronic library (e-prints)

Article

Hein, Z., Uchtenhagen, H., Abualrous, E.T., Saini, S.K., Janssen, L., Van Hateren, A., Wiek, C., Hanenberg, H., Momburg, F., Achour, A., Elliott, T., Springer, S. and Boulanger, D. (2014) Peptide-independent stabilization of MHC class I molecules breaches cellular quality control. Journal of Cell Science, 127, (13), 2885-2897. (doi:10.1242/jcs.145334). (PMID:24806963).
Gao, Yifang, Workman, Sarita, Gadola, Stephan, Elliott, Tim, Grimbacher, Bodo and Williams, Anthony P. (2014) Common variable immunodeficiency is associated with a functional deficiency of invariant natural killer T cells. Journal of Allergy and Clinical Immunology, 133, (5), 1420-1428.e1. (doi:10.1016/j.jaci.2013.10.059). (PMID:24582167).
Wang, Junwen, Bailey, Alistair, van Hateren, Andy, Elliott, Tim and Werner, Jörn M. (2014) Two polymorphisms facilitate differences in plasticity between two chicken major histocompatibility complex class I proteins. PLoS ONE, 9, (2), 1-11. (doi:10.1371/journal.pone.0089657). (PMID:24586943).
Van Hateren, A., Carter, R., Bailey, A., Kontouli, N., Williams, A.P., Kaufman, J. and Elliott, T.J. (2013) A mechanistic basis for the co-evolution of chicken tapasin and major histocompatibility complex class I (MHC I) proteins. Journal of Biological Chemistry, n/a, n/a. (doi:10.1074/jbc.M113.474031). (PMID:24078633).
Reeves, E., Edwards, C.J., Elliott, T. and James, E. (2013) Naturally occurring ERAP1 haplotypes encode functionally distinct alleles with fine substrate specificity. Journal of Immunology, 191, (1), 35-43. (doi:10.4049/jimmunol.1300598). (PMID:23733883).
James, E., Bailey, I., Sugiyarto, G. and Elliott, T. (2013) Induction of protective antitumor immunity through attenuation of ERAAP function. Journal of Immunology, 190, (11), 5839-5846. (doi:10.4049/jimmunol.1300220). (PMID:23610143).
James, E., Reeves, E., Colebatch, A.N., Elliott, T. and Edwards, C.J. (2013) Functionally distinct ERAP1 haplotype combinations define individuals with Ankylosing Spondylitis (P5047). Journal of Immunology, 190, (111.6)
Chinnery, Fay, King, Catherine A, Elliott, Tim, Bateman, Andrew R and James, Edward (2012) Viral antigen mediated NKp46 activation of NK cells results in tumor rejection via NK-DC crosstalk. Oncolmmunology , 1, (6), 874-883. (doi:10.4161/onci.20636). (PMID:23162755).
Fairbairn, N., Light, R.A., Carter, R., Fernandes, R., Kanaras, A.G., Elliott, T.J., Somekh, M.G., Pitter, M.C. and Muskens, O.L. (2012) Spatial modulation microscopy for real-time imaging of plasmonic nanoparticles and cells. Optics Letters, 37, (15), 3015-3017. (doi:10.1364/OL.37.003015).
Jayawardena, Janitha and Elliott, Tim (2012) The multidisciplinary management of non-melanoma conchal bowl skin cancer. The Australasian Journal of Dermatology (doi:10.1111/j.1440-0960.2012.00906.x). (PMID:22672097).
Mant, Alexandra, Chinnery, Fay, Elliott, Tim and Williams, Anthony P. (2012) The pathway of cross-presentation is influenced by the particle size of phagocytosed antigen. Immunology, 136, (2), 163-175. (doi:10.1111/j.1365-2567.2012.03558.x). (PMID:22260486).
Galea, Ian, Stasakova, Jana, Dunscombe, Melanie S., Ottensmeier, Christian H., Elliott, Tim and Thirdborough, Stephen M. (2012) CD8(+) T-cell cross-competition is governed by peptide-MHC class I stability. European Journal of Immunology, 42, (1), 256-263. (doi:10.1002/eji.201142010). (PMID:22002320).
Garstka, Malgorzata Anna, Fritzsche, Susanne, Lenart, Izabela, Hein, Zeynep, Jankevicius, Gytis, Boyle, Louise H., Elliott, Tim, Trowsdale, John, Antoniou, Antony N., Zacharias, Martin and Springer, Sebastian (2011) Tapasin dependence of major histocompatibility complex class I molecules correlates with their conformational flexibility. The FASEB Journal, 25, (11), 3989-3998. (doi:10.1096/fj.11-190249). (PMID:21836024).
Dalchau, Neil, Phillips, Andrew, Goldstein, Leonard D., Howarth, Mark, Cardelli, Luca, Emmott, Stephen, Elliott, Tim and Werner, Joern M. (2011) A peptide filtering relation quantifies MHC class I peptide optimization. PLoS Computational Biology, 7, (10), e1002144-[14pp]. (doi:10.1371/journal.pcbi.1002144). (PMID:22022238).
Dragovic, Srdjan M., Hill, Timothy, Christianson, Gregory J., Kim, Sungjune, Elliott, Tim, Scott, Diane, Roopenian, Derry C., Van Kaer, Luc and Joyce, Sebastian (2011) Proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with antigen processing control CD4+ Th cell responses by regulating indirect presentation of MHC class II-restricted cytoplasmic antigens. Journal of Immunology, 186, (12), 6683-6692. (doi:10.4049/jimmunol.1100525). (PMID:21572029).
James, Edward, Yeh, Alex, King, Cathy, Korangy, Firouzeh, Bailey, Ian, Boulanger, Denise S., Van den Eynde, Benoît J., Murray, Nicholas and Elliott, Tim J. (2010) Differential suppression of tumor-specific CD8+ T cells by regulatory T cells. Journal of Immunology, 185, (9), 5048-5055. (doi:10.4049/​jimmunol.1000134). (PMID:20921533).
Van Hateren, A., James, E., Bailey, A., Phillips, A., Dalchau, N. and Elliott, T. (2010) The cell biology of major histocompatibility complex class I assembly: towards a molecular understanding. Tissue Antigens, 76, (4), 259-75. (doi:10.1111/j.1399-0039.2010.01550.x). (PMID:21050182).
Fadda, Lena, Borhis, Gwenoline, Ahmed, Parvin, Cheent, Kuldeep, Pageon, Sophie V., Cazaly, Angelica, Stathopoulos, Stavros, Middleton, Derek, Mulder, Arend, Claas, Frans H.J., Elliott, Tim, Davis, Daniel M., Purbhoo, Marco A. and Khakoo, Salim I. (2010) Peptide antagonism as a mechanism for NK Cell activation. Proceedings of the National Academy of Sciences of the United States of America, 107, (22), 10160-10165. (doi:10.1073/pnas.0913745107). (PMID:20534579).
Boulanger, Denise S.M., Oliveira, Roberta, Ayres, Lisa, Prior, Stephen H., James, Edward, Williams, Anthony P. and Elliott, Tim (2010) Absence of tapasin alters immunodominance against a lymphocytic choriomeningitis virus polytope. Journal of Immunology, 184, (1), 73-83. (doi:10.4049/jimmunol.0803489).
Van Hateren, Andrew, Bailey, Andrew and Elliott, Tim (2010) The cell biology of MHC class I assembly: towards a molecular understanding. Tissue Antigens (In Press).
Howe, Christopher, Garstka, Malgorzata, Al-Balushi, Mohammed, Ghanem, Esther, Antoniou, Antony N., Fritzsche, Susanne, Jankevicius, Gytis, Kontouli, Nasia, Schneeweiss, Clemens, Williams, Anthony, Springer, Sebastian and Elliott, Tim (2009) Calreticulin-dependent recycling in the early secretory pathway mediates optimal peptide loading of MHC class I molecules. EMBO Journal, 28, (23), 3730-3744. (doi:10.1038/emboj.2009.296).
Zhang, Yinan, Kozlov, Guennadi, Poscanschi, Cosmin L., Brockmeier, Ulf, Ireland, Breanna S., Maattanen, Pekka, Howe, Chris, Elliott, Tim, Gehring, Kalle and Williams, David B. (2009) ERp57 does not require interactions with calnexin and calreticulin to promote assembly of class I histocompatibility molecules and it enhances peptide loading independently of its redox activity. Journal of Biological Chemistry, 284, (15), 10160-10173. (doi:10.1074/jbc.M808356200).
Leung, Leo, Tomassi, Cyrille, Van Beneden, Katrien, Decruy, Tine, Trappeniers, Matthias, Elewaut, Dirk, Gao, Yifang, Elliott, Tim, Al-Shamkhani, Aymen, Ottensmeier, Christian, Werner, Jörn M., Williams, Anthony, Van Calenbergh, Serge and Linclau, Bruno (2009) The synthesis and in vivo evaluation of 2,2-difluoro KRN7000. ChemMedChem, 4, (3), 329 -334. (doi:10.1002/cmdc.200800348 ).
Elliott, Tim (2009) More images that yet fresh images beget. Immunity, 30, (1), 1-2. (doi:10.1016/j.immuni.2008.12.011).
Leung, Leo, Tomassi, Cyrille, Van Beneden, Katrien, Decruy, Tine, Elewaut, Dirk, Elliott, Tim, Al-Shamkhani, Aymen, Ottensmeier, Christian, Van Calenbergh, Serge, Werner, Joern, Williams, Tony and Linclau, Bruno (2008) Synthesis and in vivo evaluation of 4-deoxy-4,4-difluoro-KRN7000. Organic Letters, 10, (20), 4433-4436. (doi:10.1021/ol801663m).
Trappeniers, Matthias, Goormans, Stijn, Van Beneden, Katrien, Decruy, Tine, Linclau, Bruno, Al-Shamkhani, Aymen, Elliott, Tim, Ottensmeier, Christian, Werner, Joern M., Elewaut, Dirk and Van Calenbergh, Serge (2008) Synthesis and in vitro evaluation of α-GalCer epimers. ChemMedChem, 3, (7), 1061-1070. (doi:10.1002/cmdc.200800021).
Thirdborough, Stephen M., Roddick, Joanne S., Radcliffe, Joanna N., Howarth, Mark, Stevenson, Freda K. and Elliott, Tim (2008) Tapasin shapes immunodominance hierarchies according to the kinetic stability of peptide-MHC class I complexes. European Journal of Immunology, 38, (2), 364-369. (doi:10.1002/eji.200737832). (PMID:18196518).
Purcell, A.W. and Elliott, T. (2008) Molecular machinations of the MHC-I peptide loading complex. Current Opinion in Immunology, 20, (1), 75-81.
Taraban, Vadim Y., Martin, Sonya, Attfield, Kathrine E., Glennie, Martin J., Elliott, Tim, Elewaut, Dirk, Van Calenbergh, Serge, Linclau, Bruno and Al-Shamkhani, Aymen (2008) Invariant NKT cells promote CD8(+) cytotoxic T cell responses by inducing CD70 expression on dendritic cells. Journal of Immunology, 180, (7), 4615-4620. (PMID:18354184).
Taylor, Mark, Bolton, Louise M., Johnson, Peter, Elliott, Tim and Murray, Nick (2007) Breast cancer is a promising target for vaccination using cancer-testis antigens known to elicit immune responses. Breast Cancer Research, 9, (4, R46), 7pp. (doi:10.1186/bcr1749).
Mimura, Yusuke, Mimura-Kimura, Yuka, Doores, Katie, Golgher, Denise, Davis, Benjamin G., Dwek, Raymond A., Rudd, Pauline M. and Elliott, Tim (2007) Folding of an MHC class II-restricted tumor antigen controls its antigenicity via MHC-guided processing. Proceedings of the National Academy of Sciences of the USA, 104, (14), 5983-5988. (doi:10.1073/pnas.0701307104).
Mant, Alexandra, Tourniaire, Guilhem, Diaz-Mochon, Juan J., Elliott, Tim J., Williams, Anthony P. and Bradley, Mark (2006) Polymer microarrays: identification of substrates for phagocytosis assays. Biomaterials, 27, (30), 5299-5306. (doi:10.1016/j.biomaterials.2006.04.040). (PMID:16808972).
Glithero, Ann, Tormo, Jose, Doering, Klaus, Kojima, Mayumi, Jones, E. Yvonne and Elliott, Tim (2006) The crystal structure of H-2D(b) complexed with a partial peptide epitope suggests a major histocompatibility complex class I assembly intermediate. Journal of Biological Chemistry, 281, (18), 12699-12704. (doi:10.1074/jbc.M511683200).
Glithero, Ann, Tormo, Jose, Doering, Klaus, Kojima, Mayumi, Jones, E. Yvonne and Elliott, Tim (2006) The crystal structure Of H-2Db complexed with a partial peptide epitope suggests an MHC class I assembly-intermediate. The Journal of Biological Chemistry, 281, (18), 12699-12704. (doi:10.1074/jbc.M511683200).
Elliott, T. and Neefjes, J. (2006) The complex route to MHC class I-peptide complexes. Cell, 127, (2), 249-251. (doi:10.1016/j.cell.2006.10.001).
Elliott, Tim (2006) The 'chop-and-change' of MHC class I assembly. Nature Immunology, 7, (1), 7-9. (doi:10.1038/ni0106-7).
Brooks, Colin R., Elliott, Tim, Parham, Peter and Khakoo, Salim I. (2006) The inhibitory receptor NKG2A determines lysis of vaccinia virus-infected autologous targets by NK cells. Journal of Immunology, 176, (2), 1141-1147.
Doores, Katie J., Mimura, Yusuke, Dwek, Raymond A., Rudd, Pauline M., Elliott, Tim and Davis, Benjamin G. (2006) Direct deprotected glycosyl-asparagine ligation. Chemical Communications, (13), 1401-1403. (doi:10.1039/b515472c).
Mimura, Yusuke, Golgher, Denise, Mimura-Kimura, Yuka, Dwek, Raymond A., Rudd, Pauline M. and Elliott, Tim (2005) Immunogenicity of calreticulin-bound murine leukemia virus glycoprotein gp90. Glycobiology and Medicine, 564, 85-94. (doi:10.1007/0-387-25515-X_13).
Howarth, M. and Elliott, T. (2004) The processing of antigens delivered as DNA vaccines. Immunological reviews, 199, (1), 27-39. (doi:10.1111/j.0105-2896.2004.00141.x).
Gao, B., Williams, A., Sewell, A. and Elliott, T. (2004) Generation of a functional, soluble tapasin protein from an alternatively spliced mRNA. Genes & Immunity, 5, (2), 101-108. (doi:10.1038/sj.gene.6364043).
Yingyongnarongkul, Boon-ek, Howarth, Mark, Elliott, Tim and Bradley, Mark (2004) Solid-phase synthesis of 89 polyamine-based cationic lipids for DNA delivery to mammalian cells. Chemistry: A European Journal, 10, (2), 463-473. (doi:10.1002/chem.200305232).
Howarth, Mark, Williams, Anthony, Tolstrup, Anne B. and Elliott, Tim (2004) Tapasin enhances MHC class I peptide presentation according to peptide half-life. Proceedings of the National Academy of Sciences of the United States of America, 101, (32), 11737-11742. (doi:10.1073/pnas.0306294101).
Bird, Lucy A., Peh, Chen Au, Kollnberger, Simon, Elliott, Tim, McMichael, Andrew J. and Bowness, Paul (2003) Lymphoblastoid cells express HLA-B27 homodimers both intracellularly and at the cell surface following endosomal recycling. European Journal of Immunology, 33, (3), 748-759. (doi:10.1002/eji.200323678).
Antoniou, Antony N., Powis, Simon J. and Elliott, Tim (2003) Assembly and export of MHC class I peptide ligands. Current Opinion in Immunology, 15, (1), 75-81. (doi:10.1016/S0952-7915(02)00010-9).
Williams, Anthony P., Peh, Chen Au, Purcell, Anthony W., McCluskey, James and Elliott, Tim (2002) Optimization of the MHC class I peptide cargo is dependent on tapasin. Immunity, 16, (4), 509-520. (doi:10.1016/S1074-7613(02)00304-7).
Gao, Bin, Adhikari, Raju, Howarth, Mark, Nakamura, Kimitoshi, Gold, Marielle C., Hill, Ann B., Knee, Rai, Michalak, Marek and Elliott, Tim (2002) Assembly and antigen-presenting function of MHC class I molecules in cells lacking the ER chaperone calreticulin. Immunity, 16, (1), 99-109. (doi:10.1016/S1074-7613(01)00260-6).
Williams, A., Peh, C.A. and Elliott, T. (2002) The cell biology of MHC class I antigen presentation. Tissue Antigens, 59, (1), 3-17. (doi:10.1034/j.1399-0039.2002.590103.x).
Wormald, Mark R., Petrescu, Andrei J., Pao, Ya-Lan, Glithero, Ann, Elliott, Tim and Dwek, Raymond A. (2002) Conformational studies of oligosaccharides and glycopeptides: complementarity of NMR, X-ray crystallography, and molecular modelling. Chemical Reviews, 102, (2), 371-386. (doi:10.1021/cr990368i).
Antoniou, Antony N., Ford, Stuart, Alphey, Magnus, Osborne, Andrew, Elliott, Tim and Powis, Simon J. (2002) The oxidoreductase ERp57 efficiently reduces partially folded in preference to fully folded MHC class I molecules. The EMBO Journal, 21, (11), 2655-2663. (doi:10.1093/emboj/21.11.2655).
Golgher, Denise, Jones, Emma, Powrie, Fiona, Elliott, Tim and Gallimore, Awen (2002) Depletion of CD25+ regulatory cells uncovers immune responses to shared murine tumor rejection antigens. European Journal of Immunology, 32, (11), 3267-3275. (doi:10.1002/1521-4141(200211)32:11<3267::AID-IMMU3267>3.0.CO;2-1).
Kastrup, Ingelise Bjerring, Andersen, Mads Hald, Elliott, Tim and Haurum, John S. (2001) MHC-restricted T cell responses against posttranslationally modified peptide antigens. Advances in Immunology, 78, 267-289. (doi:10.1016/S0065-2776(01)78006-6).
Godkin, Andrew J., Smith, Katherine J., Willis, Anthony, Tejada-Simon, Maria V., Zhang, Jingwu, Elliott, Tim and Hill, Adrian V.S. (2001) Naturally processed HLA class II peptides reveal highly conserved immunogenic flanking region sequence preferences that reflect antigen processing rather than peptide-MHC interactions. Journal of Immunology, 166, (11), 6720-6727.
Norbury, Christopher C., Princiotta, Michael F., Bacik, Igor, Brutkiewicz, Randy R., Wood, Phillip, Elliott, Tim, Bennink, Jack R. and Yewdell, Jonathan W. (2001) Multiple antigen-specific processing pathways for activating naive CD8+ T cells in vivo. Journal of Immunology, 166, (7), 4355-4362.
Golgher, Denise, Korangy, Firouzeh, Gao, Bin, Gorski, Kevin, Jaffee, Elizabeth, Edidin, Michael, Pardoll, Drew M. and Elliott, Tim (2001) An immunodominant MHC class II-restricted tumor antigen is conformation dependent and binds to the endoplasmic reticulum chaperone, calreticulin. Journal of Immunology, 167, (1), 147-155.
Rudd, Pauline M., Elliott, Tim, Cresswell, Peter, Wilson, Ian A. and Dwek, Raymond A. (2001) Glycosylation and the immune system. Science, 291, (5512), 2370-2376. (doi:10.1126/science.291.5512.2370).
Rice, Jason, Elliott, Tim, Buchan, Sarah and Stevenson, Freda K. (2001) DNA fusion vaccine designed to induce cytotoxic T cell responses against defined peptide motifs: implications for cancer vaccines. Journal of Immunology, 167, (3), 1558-1565.
Elliott, Tim, Bonneville, Marc, Kruisbeek, Ada, Walker, Paul R., Glaichenhaus, Nicolas, Rowland-Jones, Sarah, Casanova, J.L., Liu, Ying, Wood, Kathryn, Bushell, Andrew and Green, Allison (2001) Paper Alert: Immunology. Current Opinion in Immunology, 13, (2), 121-128. (doi:10.1016/S0952-7915(00)00192-8).

Book Section

Fairbairn, Natasha, Fernandes, Rute, Carter, Rachel, Elliot, Timothy J., Kanaras, Antonios G. and Muskens, Otto L. (2013) Single-nanoparticle detection and spectroscopy in cells using a hyperspectral darkfield imaging technique. In, Proceedings SPIE 8595: Colloidal Nanocrystals for Biomedical Applications VIII. SPIE Photonics West San Francisco, US, SPIE: The International Society for Optics and Photonics, 859501-859501. (doi:10.1117/12.981941).

Conference or Workshop Item

Jones, Emma, Golgher, Denise, Simon, Anna Katharina, Dahm-Vicker, Michaela, Screaton, Gavin, Elliott, Tim and Gallimore, Awen (2004) The influence of CD25+ cells on the generation of immunity to tumour cell lines in mice. In, Symposium on Cancer and Inflammation, London, UK, 12 - 14 Nov 2002. London, UK, Novartis Foundation, 149-152.
 

Research

Research Interests

Cytotoxic T cells (CTL) are an important arm of our immune defence against intracellular pathogens such as viruses, bacteria and parasites and can provide protection against the development of tumours. The picture to the right shows a swarm of CTL (coloured in white) attacking a tumour cell (coloured in orange). The outcome of this attack will be the destruction of the tumour cell. CTL recognise fragments of protein antigens (epitopes), derived from pathogens or tumours, bound to polymorphic receptor molecules encoded by the Major Histocompatibility Complex (class I) on the surface of infected cells.

The process of generating peptide fragments from pathogen proteins is known as antigen processing, and the formation of a complex, between these peptides and MHC class I molecules, which can be seen by circulating CTL is known as antigen presentation. It is the point where these two processes meet that has occupied me over the past ten yearsHere, polypeptide fragments containing CTL epitopes are transported from the cytosol, where they are made, into the endoplasmic reticulum (ER) where MHC class I molecules are synthesised. This requires a specialised peptide transporter - the recently discovered Transporter Associated with Antigen Processing or TAP. Once in the ER the polypeptide fragments can be trimmed to an optimal size for binding to newly synthesised MHC class I molecules. A process of molecular editing follows in order to ensure that only the most stable peptide:MHC complexes are released to the cell surface. Thus, intracellular peptide loading could be a major factor in determining the immunodominance of some peptide epitopes over others : watch the video made by Diego Arrosi and David Williams in Toronto for a great introduction to the subject (http://vimeo.com/27074960)

Our current research programme encompasses themes within the biology of antigen processing and presentation and immunity to tumours

Understanding the intracellular assembly of class I MHC molecules at the atomic level and its significance in controlling CTL responses in vivo

In the endoplasmic reticulum, class I MHC molecules are assembled with antigenic peptides while they are bound to a number of other proteins. These include both class I MHC-specific cofactors (TAP and tapasin) and cofactors with more general functions (calreticulin and ERp57). We have shown that the failure of class I molecules to interact with all of these cofactors results in the assembly of unstable class I heavy chain: beta-2 m dimers which are released into the secretory pathway before they have acquired an optimal peptide ligand and are functionally useless. Our experiments have also suggested that the loading of class I molecules is a two-stage process that involves an initial assembly step with low affinity, non-stabilising peptides followed by an optimisation step involving the intracellular cofactors tapasin, calreticulin and ERp57.

We have shown that tapasin is the primary editor of the peptide repertoire presented by MHC class I molecules and are currently pursuing its precise molecular mechanism using a combination of molecular dynamics modeling, molecular systems biology (a collaboration with A Microsoft Research and NMR (a collaboration with Joern Werner at the School of Biological Sciences along with standard biochemical techniques. We are investigating the importance of tapasin editing in establishing immunodominance in vivo, and are now able to relate the intracellular loading process to cytotoxic T cell responses to vaccine-encoded epitopes. These experiments identify tapasin as a potential pharmacological target for modulating the specificity and intensity of immune responses to vaccines.

We are also learning how calreticulin functions to improve intracellular peptide loading in collaboration with Sebastian Springer at Jacobs University Bremmen and David Williams at the University of Toronto

Other Collaborators include: Marek Michalak, University of Alberta, Canada; Jim McCluskey, University of Melbourne, Australia; Chen Au Peh, University of Adelaide, Australia; Jim Kaufman, BBSRC Compton, UK; Keith Gould, University of London, UK; Simon Powis, University of St Andrews, UK; Joern Werner, University of Southampton; Luca Cardelli and Andrew Phillips, Microsoft UK, Cambridge.

Key reviews and commentary:

These two can be read as a series:
The Cell Biology of MHC class I assembly. Williams A, Peh C A and Elliott T. (2002). Tissue Antigens. 59: 3-17.
The Cell Biology of MHC class I assembly: Towards a molecular understanding. Van Hateren A, Bailey A, Elliott T. (2010). Tissue Antigens 76(4):259-75.
The complex Route to MHC class I-Peptide complexes. T Elliott and J Neefjes. (2006). Cell 127: 249-251.
The 'chop-and-change' of MHC class I assembly.Elliott T. (2006). Nat Immunol. Jan;7(1):7-9.
The optimization of peptide cargo bound to MHC class I molecules by the peptide-loading complex. Elliott T and Williams A (2005). Immunol Rev.;207:89-99
The processing of antigens delivered as DNA vaccines. Howarth M and Elliott T (2004) Immunol Rev. 199:27-39.

The role of post-translational events on processing and presentation

In addition to class I assembly, the other event at the junction between antigen processing and presentation is the trimming of polypeptides in the ER to give optimal sized fragments for binding to MHC class I: a fact that we established in 1994. We have investigated the extent to which ER trimmase activities act on all glycoproteins in the ER which led us to the discovery that the glycans attached to glycoproteins can regulate their presentation by affecting the rate or quite possibly the site of their degradation. The rapid degradation that results from deglycosylation of a potential antigen occurs in the early secretory pathway and leads to the generation of peptide epitopes. This establishes the ER as an alternative site for antigen processing, and reveals that hidden glycoprotein epitopes can be uncovered depending on the glycosylation state of the antigen.
We have also found that MHC class II-restricted responses to a tumour antigen can be controlled by the intracellular folding environment of the tumour cell in which it is expressed, and that immunodominance to this antigen is achieved via MHC-guided processing of the misfolded protein. We are in the process of identifying the biochemical pathway in the tumour cell line that gives rise to the immunogenic conformation of the antigen with a view to finding new targets to indirectly enhance the immunogenicity of “silent” tumour antigens.

Regulatory T cells in tumour immunity

Immunological defence mechanisms that are normally thought to protect us from infections are now also thought to eliminate unwanted cells in the body, particularly those that are unable to stop proliferating (e.g. tumour cells). This is a form of reactivity towards "self" called autoimmunity. Excessive activation of self-reactive immune cells can lead to a pathological condition called autoimmune disease where the otherwise helpful destructive powers of the immune system become aberrantly focussed on normal, healthy cells in the body.

The way in which self-reactive immune cells are controlled, and in particular, how potentially dangerous reactivities are suppressed in healthy individuals is largely unknown. Recently, a population of suppressor immune cells (called regulatory T cells or Tregs) has been identified that seems to keep some kinds of autoimmune disease at bay in experimental mice. We have shown that the same population of cells prevents experimental mice from staging an immune attack against tumour cells so that when we get rid of them, these mice are able to protect themselves against the growth of a transplantable tumour.

We have also found that the immune response generated in these mice is broader that that generated with other more conventional anti-tumour vaccines and results in protection against a wide variety of experimental tumours from colon cancer to lymphoma. We have identified the epitope recognized by cross-protective cytotoxic T cells primed in the absence of Treg and are currently investigating the immunological basis of the differential suppression we see in tumour bearing mice.

Collaborators include: Awen Gallimore, University of Cardiff, Wales; Benoit Van den Eynde, Ludwig Institute Brussels, Belgium.

Key review:

The influence of CD25+ cells on the generation of immunity to tumour cell lines in mice. Jones E, Golgher D, Simon K., Dahm-Vicker M, Screaton G, Elliott T and Gallimore A. (2004). Novartis Found Symp.;256:149-52; discussion 152-7, 259-69.

Funding:

• Cancer Research-UK
• The Wellcome Trust, UK
• Association of International Cancer Research
• The Carlsberg-Wellcome Foundation, DK
• The MRC, UK
• The University of Southampton, UK

Postgraduate opportunities

We usually have space for 1-2 graduate students each year. If you are interested in our work and would like to find out about doing postgraduate research in my lab, begin your enquiries well in advance. It would help to contact me for an informal chat in the early months of your final year at University.

Other Userful sites

HLA binding predictions

Basic Immunology textbook

Academic unit:  Cancer Sciences

Cytotoxic T Cells (CTL)

Cytotoxic T Cells (CTL)

Antigen processing and presentation

Antigen processing and presentation

Calreticulin Functions

Calreticulin Functions

MHC class II-restricted responses

MHC class II-restricted responses

Responsibilities

Faculty of Medicine

Faculty of Medicine Associate Dean (Research)
Research Management Committee (Chair)
UoA 1 REF champion
Director of the 4yr Integrated PhD Programme
Deputy Director of the Institute for Life Sciences

National and International responsibilities

Co-Chair of the Wellcome Trust Expert Review Group 4
Leukaemia & Lymphoma Research (Scientific Committee member)
Chair of Wessex Medical Research scientific advisory board
Clinical Trial External Monitor (University of Cardiff Hospitals Trust)
Groningen Medical Centre, NL (Scientific advisory board (Member)

Teaching Responsibilities


Lectures in Antigen Processing and presentation to undergraduate Medical Students (BM3019) and Biological Scientists (BS3037).

BM Guest Lecture “Why (I) do biomedical research”

PGR Induction and orientation to research in the Faculty

Transferrable skills training seminars including “Good Scientific Practice”, “How to write a thesis”, “What is research?”

Contact

Professor Tim Elliott
Somers Cancer Research Building
Southampton General Hospital
Mail Point 824
Tremona Road
Southampton
SO16 6YD

Phone: 023 8120 6193
Fax: 023 8120 5152
Email: T.J.Elliott@soton.ac.uk

Room Number: SGH/CSB/MP824