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The Immunogenomics Group

Immune Tolerance & Signalling Laboratory

Leader: Professor Chris Goodnow

 

Cell-Mediated Immunogenomics

Dr Ed Bertram

 

The Immunogenomics Group in the Division of Immunology and Genetics of The John Curtin School is combining the mutagenesis approach with other genetic, biochemical and cell biological strategies to identify and understand how the immune system is regulated to prevent or correct unwanted immune responses.

 

Our research aims to understand how immune cells make a fundamental decision: either to fight or to disarm. The process of deciding which immune cells should fight and which should disarm is key to our ability to resist infection and parasitism. Mistakes in this process result in autoimmune diseases, allergy, lymphoma, and leukemia. Moreover, drugs and other ways to alter fight or disarm decisions are sorely needed to improve the success of organ transplantation and treatment of autoimmune diseases and metastatic cancer.

The immune system is made up of billions of immune cells called lymphocytes. By a remarkable gene shuffling process akin to a poker machine, each lymphocyte carries a unique receptor, enabling every lymphocyte to detect a different set of molecules termed antigens. Some lymphocytes have receptors for foreign antigens that are unique parts of the molecular makeup of different infectious organisms. When these rare lymphocytes bind a foreign antigen during an infection, they receive a signal to fight. The lymphocyte first multiplies to make many clones of itself, and then the cells elaborate destructive compounds that neutralize the infectious antigen.

By chance, other lymphocytes carry receptors for self antigens, ie. parts of our own normal tissues and body fluids. When a lymphocyte binds a self antigen it normally receives a signal to disarm. Instead of multiplying and producing destructive compounds, the lymphocyte either commits cell suicide by apoptosis or the cell disarms itself by becoming functionally tolerant, ie. less responsive to antigens and less able to multiply or produce destructive compounds.

For a long time it was not possible to see how self-reactive lymphocytes disarm themselves. Our laboratory has developed ways to visualize this process in genetically modified laboratory mice called transgenic mice. By studying cells in the transgenic mice, we have discovered that each immune cell must run through a complex series of fight or disarm checkpoints before it can be fully launched into an immune response. In some ways, the process resembles the sequence of fight/disarm decisions in a military missile launch, which serve a similar purpose of preventing friendly fire.

Members of the laboratory are deciphering different fight/disarm checkpoint processes, using a combination of biochemistry, cellular immunology, genetic analysis, and transgenesis. At each of these checkpoints, we are focusing much of our work on elucidating how it is that antigen receptors on lymphocytes can trigger several different cell fates ranging from cell proliferation to cell death. Three examples of our work that have been published this year are summarized below.

T cell tolerance and destruction of pancreatic islets

The cellular and molecular processes regulating CD4 T cell responses to self antigens that are restricted to specific organs (organ-specific tolerance and autoimmunity) are being investigated through an NIH and JDRF-funded project involving a unique transgenic mouse model. The core of this model is a "TCR-transgenic" mouse where most CD4 T cells react with a model antigen, and where the model antigen is made by pancreatic islet beta cells. The islet-reactive T cells are normally regulated so that they can cause inflammation of the pancreatic islets, but this inflammation does not progress to diabetes or autoantibody production. This regulation is broken by one or more genes from the NOD strain, an excellent animal model for spontaneous Type 1 diabetes in humans, but it has been difficult to identify what regulatory processes are primarily affected. Dr Sylvie Lesage has discovered that one of the main actions of the diabetes susceptibility genes is to dramatically reduce the efficiency of islet-reactive T cell deletion in the thymus. Some of the diabetes genes act within the islet reactive T cells, interfering with the normal processes that censor these forbidden clones of cells. By revealing the primary cell regulatory processes that are disturbed by diabetes genes, this experimental model provides a unique opportunity to define the molecular pathways regulating diabetes and other autoimmune diseases.

Memory receptor tail

Our ability to resist infection stems from a cardinal property of the immune system, namely an ability to mobilise a much higher and faster antibody response when the antigens that make up a virus or bacteria are seen a second time. This phenomenon of immunological memory lasts for years after infection or immunisation, but its cellular and molecular basis is still poorly understood. Mr Stephen Martin has defined a key role for the 'BCR Tail sequence' in promoting memory-level antibody responses. It has been known for many years that B cells switch portions of the antibodies they produce from IgM to IgG as part of the memory process. Among the many changes that result from switching to IgG, one intriguing change is in the sequence and length of the antibody segment that serves as a receptor for antigen - the transmembrane and cytoplasmic tail. Through a sophisticated combination of transgenic mice and in vivo immunological analyses, Steve has shown that the memory-type IgG tail dramatically increases the number of progeny cells that are formed by proliferation of initially rare B cells that react to antigen. This finding explains the memory phenomenon by a localizing it to a precise sequence of amino acids and a specific process-augmenting the clonal burst. This finding has wide implications for vaccination, allergy and autoimmunity, where B cells bearing the memory tail are formed.

Maintaining an army reserve

Infectious disease agents are constantly changing, with new or variant forms arising constantly, so that it is impossible to anticipate the form or fingerprint of an infection in advance. To tackle this problem, the immune system must keep on hand a reserve of billions of B lymphocytes marching about the body. Each cell carries a different antibody so that by chance at least one of these antibodies will be able to recognize and destroy any possible infectious agent. A central issue is how the size of this reserve population is regulated: immunodeficiency diseases result from it becoming too small, while common forms of lymphoma and leukemia result from it growing out of control. Through analysis of an ENU-induced mouse mutation, Ms Lisa Miosge has defined a critical regulator of this process, NfkappaB2 showing that this DNA-binding transcription factors acts within each B cell to promote persistence in the reserve population of recirculating mature B cells. This result helps explain how activating mutations in NfkappaB2, which have previously been demonstrated in B cell lymphoma, can contribute to the uncontrolled accumulation of these cells. Together with other research published at the same time, Lisa's work establishes that NfkappaB2 mediates the survival-promoting effects of a newly discovered B cell growth factor, BAFF/Blyss.