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Cambridge Immunology Network



The adaptive immune system allows vertebrate hosts to mount highly specific responses against invading pathogens. Importantly, by generating memory of the primary encounter protection against re-infection with the same organism is established. MHC class II molecules play a central role in this process by associating with components of the pathogen and presenting them to specific T helper lymphocytes. Our work is focused on understanding how pathogens interact with the host immune system and in particular the MHC antigen presentation pathways.

MHC class II antigen presentation is a highly co-ordinated process requiring chaperone assisted loading of receptive class II complexes. Immature class II molecules are first synthesised in the endoplasmic reticulum in association with invariant chain, a chaperone protein that targets folded molecules into the endocytic pathway. Here invariant chain is proteolytically removed and the class II molecules associate with peptides derived from degraded proteins. Additional chaperone proteins help shape the repertoire of peptides that are eventually transported to the cell surface and presented to T cells. The complexity of this pathway provides pathogens with many opportunities for intervention. We have investigated the interaction of Salmonella with the MHC class II processing pathway and shown that infection results in a substantial reduction in cell surface MHC expression. This requires the function of SifA, a Salmonella encoded virulence factor. We are currently investigating the mechanism responsible for this reduction in MHC expression. Our goal is to understand how different infectious agents impinge on the host immune system.


Key publications: 

Lapaque, N. Jahnke, M. Trowsdale, J and Kelly, A. P. (2009) Salmonella regulates polyubiquitination and surface expression of MHC class II antigens. Proc Natl Acad Sci U S A. 106: 14052

Lapaque, N. Jahnke, Trowsdale, J and Kelly, A. (2009) The HLA-DRαchain is modified by poly-ubiquitination. J Biol Chem 284: 7007-16

Li, K. Anderson, K. J. Peng, Q Nobel, A.Lu, B , Kelly, AP, Wang, N, Sacks, S and Zhou, W.(2008) Cyclic AMP plays a critical role in C3a-receptor mediated regulation of dendritic cells in antigen uptake and T cell stimulation. Blood 112: 5084-94

Reinicke, A. T., Hutchinson, J. L., Magee, A. I., Mastroeni, P., Trowsdale, J. & Kelly, A. P.. (2005). "A Salmonella typhimurium effector protein SifA is modified by host cell prenylation and S-acylation machinery." J Biol Chem 280(15): 14620-7.

Mitchell, E. K., Mastroeni, P., Kelly, A. P. & Trowsdale, J.. (2004). "Inhibition of cell surface MHC class II expression by Salmonella." Eur J Immunol 34(9): 2559-67.

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