Immune Signalling Achievements, Awards & Prizes
Immune Signalling Achievements, Awards & Prizes - Research at Peter Mac
|Awards & Prizes|
|Recent Research Achievements|
|ASYMMETRIC CELL DIVISION IN LYMPHOCYTE FATE DECISIONS. |
The proliferation and differentiation of a naïve T cell is triggered by TCR signals from antigen presenting cells. However, other context-dependent events determine both the extent of activation, and the fate of the subsequent daughter cells (for instance activation or anergy; Th1 or Th2; & effector or memory). One such factor is the duration of interactions between T cells and antigen presenting cells. Early assumptions, based primarily on in vitro studies with preactivated T cells or T cell lines, were that the key TCR signaling occurred within minutes of T cell conjugation. This hypothesis was not compatible with the presiding view that an immunological synapse serves to sustain TCR signals, and indeed recent results suggest that the immunological synapse inversely correlates with TCR signaling and with the duration of T cell conjugation with the antigen presenting cell. Even more obscure at present is the role of the distal pole, a concentration of proteins at the opposite end of the immunological synapse.
It is now clear from in vivo imaging that long term interactions (several hours) of T cells with antigen presenting cells are almost invariably required for an effective immune response. We developed new systems to analyze interactions that can facilitate such long term interactions. This has led to our observations that T cells undergo asymmetric cell division while attached to an antigen presenting cell. By maintaining polarity until the point of cell division, interactions with the antigen presenting cell allow molecules at the distal pole to be segregated preferentially into the distal cell. This observation indicates that the microenvironment of a dividing T cell has the capacity to dictate the fate of each daughter cell by orchestrating protein distribution between the daughters. This notion has profound implications for T cell development, and also for leukemia. By elucidating the mechanisms and consequences of T cell asymmetric cell division, we expect to identify new means to manipulate immune function and cancer.
MOUSE MODELS TO ELUCIDATE HOW POLARITY AFFECTS IMMUNE FUNCTION AND CANCER.
We have spent considerable effort over the last five years — in collaboration with the Cell Cycle and Cancer Genetics group — toward developing mouse models with which to understand how the polarity proteins orchestrate development and function of cells in vivo, and we are now making some very interesting discoveries regarding their role in immune function. Generally, it seems that immune cells can develop in the absence of immune proteins, but the behavior of the cells upon activation is altered. These findings are particularly exciting because they show that these mouse models will make valuable tools with which to dissect the role of polarity in leukemia and lymphoma. We are now working with other researchers across Peter Mac to explore the impact of polarity disruption upon cancer progression using a number of different models of leukemia.
ILLUMINATING T CELL POLARITY AND FUNCTION.
As highlighted by a Nobel Prize to the discoverers of Green Fluorescent Protein in 2008, time-lapse, fluorescent imaging of living cells provides incredibly powerful opportunities to learn how cell behaviour is controlled. Much of our efforts in the lab involve using such approaches, facilitated by the excellent infrastructure at Peter Mac, to define the mechanisms by which cell fate is controlled. However, there continues to be a burning need to improve these technologies, and we work with our colleagues at Swinburne University of Technology on a number of such efforts. Of particular excitement is a new approach that can improve the resolution of fluorescence approximately ten-fold. The power of this advance is such that the technique has been given the name ‘Super-Resolution Microscopy’.
To enable Peter Mac researchers to utilize this technology before it becomes widely available to biologists, we are working with physicists at Swinburne to create a Super-Resolution Microscope. We were awarded funding for this project from the NHMRC in 2008.
|+61 (0)3 9656 1238|
|Dr Sarah Russell|
|Peter Mac Research Fellow|
|Dr Jane Oliaro |
|Clinical Research Fellow|
|Dr Stephen Ting|
|Senior Research Assistant|
Vanessa van Ham
|Ivan Fung Ting Hin|