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Pathogens and defence

Plenary lecture 2

Sunday, 6 September, 09:00 - 10:30 Hall 1


Cambridge Institute for Medical Research

The immunological synapse in 4D

Cytotoxic T lymphocytes (CTL) use polarized secretion to rapidly destroy virally infected and tumor cells with great specificity.   Secretion is focused at an immunological synapse formed between killer and target.   This structure provides a remarkable example of cell polarity, with membrane receptors, cell cytoskeleton and secretory organelles focused towards the point of interaction.   In order to understand how CTL provide such focused and efficient killing, we use high-resolution multi-colour imaging in 4D.  This approach continues to provide new insights into the mechanisms involved, as it provides high-resolution images across the entire cell as it prepares for attack.
Striking similarities exist between the immunological synapse, which forms between immune cells and primary cilia.  In both cases the centrosome polarizes to the plasma membrane creating a region of the plasma membrane that becomes specialized in signaling, endocytosis and exocytosis.   The extent of these similarities will be discussed in the context of how the immunological synapse might have arisen.


Gillian Griffiths' laboratory carries out research at the interface between cell biology and immunology aimed at understanding the mechanisms controlling polarised secretion from cytotoxic T lymphocytes (CTL); the killer cells of the immune system which destroy virally infected and tumor cells. These cells are intriguing as they use a modified "secretory" lysosome to deliver their lethal hit. In order to understand the cell biology of these cells the Griffiths lab pioneered the use of CTL from patients with genetic disorders to study cell biology in a specialized cell type in order to identify many of the molecular mechanisms controlling secretion. The recent focus of the lab centres on their discovery that the centrosome has a unique role in driving polarized secretion at the immunological synapse formed between cytotoxic T-cell (CTL) their targets. Her laboratory revealed striking similarities between primary cilia and the immunological synapse. This led to their recent characterization of a role for Hh signalling in centrosome polarization that has highlighted the possible origin of the immunological synapse as a modified cilium.



Imperial College, London

Hostile takeover: manipulation of mammalian cells by Salmonella

Following entry of Salmonella into host cells, this pathogen replicates in a membrane-bound compartment called the Salmonella-containing vacuole. Bacteria sense nutritional deprivation and the acidic pH of the vacuole lumen to activate the expression of the SPI-2 type III secretion system (T3SS). This forms an envelope-spanning secretion system and associated translocon pore in the vacuole membrane. Bacteria then sense the near-neutral pH of the host cell cytoplasm, which results in degradation of a bacterial membrane-bound regulatory complex, enabling the translocation of virulence proteins (effectors) through the pore and into the host cell.
Approximately 30 different effectors are translocated by the SPI-2 T3SS. These have been implicated in several physiological activities, including the control of vacuole location within the cell, maintenance of vacuole membrane integrity, bacterial replication, interference with lysosome function and immune signalling, and the induction of cytotoxicity. We are currently studying the functions of several of these effectors and in this talk I will discuss our recent progress on some of them.


David Holden is Director of the MRC Centre for Molecular Bacteriology and Infection at Imperial College London. He obtained his PhD in Microbiology from University College London. He held postdoctoral fellowships in Canada, the USA and the MRC National Institute for Medical Research, London. In 1990 he was appointed Lecturer at the Royal Postgraduate Medical School, London, becoming full Professor in 1995. Holden is best known for inventing signature-tagged mutagenesis (also known as barcoding) for identification of mutants with altered growth in mixed populations. Using this his group has identified numerous bacterial virulence genes, including those encoding the Salmonella SPI-2 type III secretion system. The group currently studies bacterial virulence mechanisms, in particular those of Salmonella.



National Cancer Institute, NIH, Frederick

Immunogenetic factors that impact the course of HIV infection

Variation in the HLA class I genes have the greatest influence on outcome after HIV infection relative to the rest of the genome. While allelic effects of these genes have been well-appreciated for over two decades, more recently it has become evident that other polymorphisms within the region also contribute to HIV control, such as those involved in regulation of HLA cell surface expression.  The HLA class I loci function as ligands for the killer immunoglobulin-like receptors (KIR) and the leukocyte immunoglobulin-like receptors (LILR), and variation in these genes in combination with that at the HLA loci can have an impact on host defense against the virus.  I will present data that emphasizes the multiple ways in which variation within/around the HLA class I loci affects their interaction with other genes, and how these interactions in turn modulate HIV control.


Dr. Mary Carrington is the Director of the Basic Science Program at the Frederick National Laboratory for Cancer Research (FNLCR), where she is responsible for the oversight of a diverse group of scientists performing investigator-initiated basic research in cancer and AIDS. She is also a Senior Principal Scientist at the National Cancer Institute and heads the HLA Immunogenetics Laboratory in the Cancer and Inflammation Program. Her primary research interests focus on the role of host genetics in cancer, autoimmunity and infectious disease pathogenesis. Dr. Carrington received her Ph.D. in Immunobiology from Iowa State University. Her postdoctoral studies took place in the Departments of Immunology and Microbiology at Duke University and the University of North Carolina, after which she joined the Immunology Department at Duke University as a faculty member. She moved to the National Cancer Institute at Frederick (now the FNLCR) in 1989. She is a member of the Steering Committee of the Ragon Institute of MGH, MIT, and Harvard, and a Visiting Professor at Harvard University.