Antigen presentation by major histocompatibility complex (MHC) class I molecules
The theme of Dr Gould's research is antigen presentation by major histocompatibility complex (MHC) class I molecules, and in particular the biochemistry and cell biology of these molecules.
MHC class I molecules present short, intracellularly derived peptides at the cell surface for possible recognition by CD8+ T lymphocytes, natural killer (NK) cells, and inhibitory receptors expressed on a variety of cells of the immune system. The peptides, usually 8-10 amino acid residues long, may be derived from normal self proteins, tumour proteins, or from pathogenic micro-organisms including viruses and bacteria. The level of expression of MHC class I molecules at the cell surface is of crucial importance for cellular recognition, even in the absence of infection or malignancy.
For each MHC class I molecule expressed on the plasma membrane, the highly polymorphic heavy chain is assembled with the conserved light chain ß2-microglobulin (ß2m) and peptide in the endoplasmic reticulum (ER) in a complex series of events that has been studied extensively. In spite of this work, a number of fundamental questions about MHC class I molecules still remain.
My current research primarily aims to address these basic questions:
1) How do different MHC class I heavy chains affect each others’ assembly, cell surface expression and function?
2) Why does possession of certain MHC class I alleles increase susceptibility to specific human inflammatory diseases?
The outline 3-D structure of an MHC class I molecule, showing the two additional linker sequences (red) in a single chain MHC class I molecule
Principal investigator
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Current Work
Current research interests focus on early events in the intracellular assembly of major histocompatibility complex (MHC) class I molecules, and in the uses of a new type of construct: single chain MHC class I molecules (see below).
Figure 1. The outline organisation of a single chain MHC class I molecule
We are using mutant forms of class I heavy chains and single chain MHC class I molecules to further dissect the early events in class I assembly, and to devise new approaches for the induction of CD8 T-cell responses.
The unique properties of single chain MHC class I molecules are also being exploited to study the molecular mechanisms of T cell and natural killer (NK) cell triggering, and to investigate the role of MHC class I folding efficiency in pre-disposition towards inflammatory diseases.
Accumulation of a single chain MHC class I molecule (green) at the interface bwteen a T cell (red) and antigen presenting cell
Key Publications (2000-present)
Choudhuri, K., D. Wiseman, M.H. Brown, K. Gould and P.A. van der Merwe. 2005
T cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 436:578-582.
Tourdot, S., M. Nejmeddine, S.J. Powis and K.G. Gould. 2005.
Different MHC class I heavy chains compete with each other for folding independently of ß2-microglobulin and peptide. J Immunol 174:925-933.
Tourdot, S., and K.G. Gould. 2002.
Competition between MHC class I alleles for cell surface expression alters CTL responses to influenza A virus. J Immunol 169:5615-5621.
Tourdot, S., S. Herath, and K.G. Gould. 2001.
Characterization of a new H-2Dk-restricted epitope prominent in primary influenza A virus infection. J Gen Virol 82:1749-1755.
Four Key Previous Publications
Sibille, C., K.G. Gould, K. Willard-Gallo, S. Thomson, A.J. Rivett, S. Powis, G.W. Butcher, and P. De Baetselier. 1995.
LMP2+ proteasomes are required for the presentation of specific antigens to cytotoxic T lymphocytes. Curr Biol 5:923-930.
Gould, K.G., H. Scotney, and G.G. Brownlee. 1991.
Characterization of two distinct major histocompatibility complex class I Kk-restricted T-cell epitopes within the influenza A/PR/8/34 virus hemagglutinin. J Virol 65:5401-5409.
Gould, K., J. Cossins, J. Bastin, G.G. Brownlee, and A. Townsend. 1989.
A 15 amino acid fragment of influenza nucleoprotein synthesized in the cytoplasm is presented to class I-restricted cytotoxic T lymphocytes. J Exp Med 170:1051-1056.
Townsend, A.R., J. Bastin, K. Gould, and G.G. Brownlee. 1986.
Cytotoxic T lymphocytes recognize influenza haemagglutinin that lacks a signal sequence. Nature 324:575-577.
