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A comparison of how HLA class I molecules on gamma delta T-cells and dendritic cells communicate the presence of infected and cancerous cells to other T-cells
Supervisors: Dr Kenth Gustafsson and Dr John Anderson
Major histocompatibility complex (MHC) genes, or HLA in humans, code for molecules that are able to present peptides from self as well as non-self proteins to T-cells. In a healthy state such presentation leads to tolerance to normal self-cells, whereas virally infected and transformed cells are destroyed (1). When a cell is infected or transformed this ‘steady-state’ of display is disturbed and can be detected by T-cells through the binding and presentation of viral or tumour cell-associated (TAA) antigens. In addition, and importantly, professional antigen presenting cells (pAPC) can take up such antigens, and process and present antigenic peptides to T-cells in an activating fashion termed cross-presentation (2).
We recently described how human gammadelta T-cells (γδT) surprisingly take up bacteria as well as fragments from pathogenic or transformed cells and then process and present peptides from associated proteins on HLA molecules to other T-cells (i.e. ab T-cells), including naïve T-cells (3). This shows that remarkably, γδT can first kill an infected or transformed target cell and then subsequently perform pAPC functions using material from the target cell, in a manner which appears to be reminiscent of DC cross-presentation pAPC functions (4). The fact that primary γδT from e.g. peripheral blood can be expanded ex vivo to large numbers has attracted considerable interest in their use in immunotherapy against tumours (and possibly infectious disease). We are now investigating how their pAPC function could be harnessed in immunotherapy situations as a convenient, target-specific, safe and efficient alternative to DC.
Whilst we now know that γδT can cross-present
soluble as well as phagocytosed antigens to other T-cells, we know nothing
about the repertoire of such antigens when presented on HLA-I molecules at the
γδT cell surface and how such repertoires compare with those on other pAPC
having taken up the same material. To
begin to address these questions, we have recently established proteomics
methods to analyse the contents of the peptide-binding pockets of human HLA-I
on γδT essentially as previously described for other cell types (5). In this project, the student will analyse the
peptide repertoires that are bound by cross-presenting HLA class I
molecules. S/he will use three sources
of peptide antigens: bead-bound viral
and tumour-associated antigen (TAA) recombinant proteins and long peptides,
cell-transfected versions of the same antigens, and γδT endogenously expressing
transduced antigen genes. These will be
fed to γδT and dendritic cells (DC), as a classical pAPC by comparison, and the
HLA-I peptide repertoires studied by elution and QToF mass spectrometry (MS/MS)
analysis and comparisons to prediction software analyses. Specific
cross-presentation pathway inhibitors will also be used to find out which
pathways is used in the γδT as compared to in the DC.
These analyses building on established technologies, should be invaluable in informing us which TAA as well viral antigens are best handled by γδT, and help to lay the foundation for improved cancer immunotherapy as well as potentially novel startegies in infectious disease treatments.
1) Donaldson JG, Williams DB. Intracellular assembly and trafficking of MHC class I molecules. Traffic. 2009 Dec;10(12):1745-52.
2) Joffre OP, Segura E, Savina A, Amigorena S. Cross-presentation by dendritic cells. Nat Rev Immunol. 2012 Jul 13;12(8):557-69.~
3) Wu Y, Wu W, Wong WM, Ward E, Thrasher AJ, Goldblatt D, Osman M, Digard P, Canaday DH, Gustafsson K. Human gamma delta T cells: a lymphoid lineage cell capable of professional phagocytosis. J Immunol. 2009 Nov 1;183(9):5622-9.
4) Himoudi N, Morgenstern DA, Yan M, Vernay B, Saraiva L, Wu Y, Cohen CJ, Gustafsson K, Anderson J. Human γδ T lymphocytes are licensed for professional antigen presentation by interaction with opsonized target cells. J Immunol. 2012 Feb 15;188(4):1708-16.
5) Bassani-Sternberg M, Barnea E, Beer I, Avivi I, Katz T, Admon A. Soluble plasma HLA peptidome as a potential source for cancer biomarkers. Proc Natl Acad Sci U S A. 2010 Nov 2;107(44):18769-76.