Research The use of HLA class I tetramers has provided important insights into the analysis of tumour specific immune response, and allowed direct demonstration of expanded populations of activated tumour specific cytotoxic T lymphocytes (CTL) in some patients with metastatic melanoma. Results in my laboratory have demonstrated that the largest expansions of tumour-specific CTL is observed in tumour-infiltrated lymph nodes, where the CTL response can seem analogous to that seen in acute viral infections, with high frequencies of activated CTL specific for a single epitope (up to 1/8 of the CD8+ cells). Our results indicate that in vivo priming of melanoma –specific CTL is a late phenomenon, since only stage II or stage IV patients have an active immune response. A complimentary line of research is the analysis of the presentation of glycolipid by CD1 molecules. The CD1 family of glycoproteins has recently been found to bind bacterial and self-glycolipids for presentation to specific T lymphocytes. CD1 restricted T lymphocyte subsets include cytolitic effector T cells and regulatory NKT cells, which can rapidly secrete large amounts of cytokines. Recent studies suggest that NKT cells are involved in autoimmunity and viral and bacterial infections, and have shown that NKT cells play an important role in tumour immunity. However, analysis of the role of CD1 has been hampered by the lack of reliable and sensitive techniques to isolate glycolipid specific T lymphocytes ex-vivo. Over the last years we have developed novel protocols for the generation of CD1/glycolipid tetramers, which allow sensitive and highly specific isolation and characterisation of CD1 restricted T lymphocytes from peripheral blood and lymphocytes. Experiments are currently in progress to assess the role of lipid specific immune responses in health and disease. Key Publications McCarthy C, Shepherd D, Fleire S, Stronge VS, Koch S, Illarionov PA, Bossi G, Denkberge G, Tarlton A, Schmidt RR, Reiter Y, Griffiths G, van der Merwe A, Besra GS, Jones EY, Batista F, Cerundolo V. The length of lipids bound to human CD1d molecules modulates the affinity of NKT cell lTCR and the threshold of NKT cell activation. J Exp Med. 2007 May; 204(5):1131-1144 Herman, JF, Silk JD, Gileadi U, Masri SH, Shepherd D, Farrand JK, Salio M, Cerundolo V. Dendritic cell function can be modulated through cooperative actions of TLR ligands and invariant NKT cells. J Immunol. 2007 Mar 1; 178(5):2721-9 Gadola SD, Silk JD, Jeans A, Illarionov PA, Salio M, Besra GS, Dwek R, Butters TD, Platt FM, Cerundolo V. Impaired selection of invariant natural killer T cells in diverse mouse models of glycosphingolipid lysosomal storage diseases. J Exp Med. 2006 Oct2; 203(10):2293-303 Smith C, Mirza F, Pasquetto V, Tscharke D, Palmowski M, Dunbar R, Sette A, Harris AL, Cerundolo V. Immunodominance of poxviral-specific CTL in a human trial of recombinant Modified Vaccinia Ankara. J Immunol. 2005 Dec 15;175(12):8431-7 Koch M, Stronge VS, Shepherd D, Gadola SD, Mathew B, Ritter G, Fersht AR, Besra GS, Schmidt RR, Jones EY, Cerundolo V. The crystal structure of human CD1d with and without alpha-galactosylceramide. Nat Immunol. 2005 Aug;6(8):819-26 |
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