We had the privilege of speaking with Dr. John Trowsdale, Emeritus Professor, specialist in Immunogenetics, in the Department of Pathology, University of Cambridge UK. Professor John Trowsdale is a world-renowned expert in the field of immunology and has made seminal contributions to our understanding of the immune system and its role in human health and disease.
In this interview, Professor Trowsdale is discussing what inspired him to specialize in this field and how he got started, as well as his views on the future of KIR typing for transplantation and potential medical applications. He also talks about other genes that may be important in transplantation and gives advice for researchers interested in this field. Finally, he talks about recent exciting developments in his research on KIR3DL3 and its potential as a target for cancer therapy.
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What inspired you to specialize in the genetics of immune receptors, and how did you get started in this field?
My first degree was in bacteriology and my PhD in bacterial genetics in 1973, when I became interested in mapping genes. After a stimulating postdoc in Paris I went to the Scripps Clinic in La Jolla and there learnt that it may be possible to apply genetics to human cells in tissue culture, at the time that cloning of human genes was just starting. I was thinking of returning to the UK and I asked Walter Bodmer if he would take me on as a postdoctoral fellow, in Oxford. He agreed and he asked me to start by cloning HLA genes. Those were exciting times as the emerging human gene sequences helped enormously to explain the molecular components of the immune system. I have to admit to having no experience with cloning DNA and I had to learn on the job with several false starts. Luckily for me Walter became head of the prestigious Cancer Research Laboraties in London where many talented researchers were on hand. We went on, collaborating with Stephan Beck, to sequence the first complete human MHC complexes and co-discovered antigen processing genes such as TAP in the MHC.
How do you see this field (KIR typing for transplantation) evolving in the future?
The precise rules for KIR/HLA mismatch, in order to lower the rate of relapse in leukaemia, remain to be more fully understood. The benefit of KIR typing for solid organ transplantation is even less advanced. There is much to learn still, such as precisely how peptides associated with HLA influence KIR, the function of KIR on CD8 T cells and their involvement in NK cell memory.
Do you see potential medical applications for KIR typing other than transplantation?
There are already indications that KIR typing may have a medical application in pregnancy as the KIR types of mother and father influence conditions such as pre-eclampsia. Another potential application is in targeted therapies for cancer, harnessing the power of NK cells. Some laboratories are exploring ways in which activating KIR may be exploited to develop a unique form of vaccination. The importance of KIR in infectious diseases is poorly understood at present as the combination of HLA variation KIR complexity makes it difficult to tease out individual effects.
Are there more genes then HLA and KIR that may be important during transplantation of stem cells or organs?
Of course, ABO blood group typing is critical and genes influencing rare blood types are of emerging interest. No other genes appear to vary as much as HLA and KIR but there are many other receptors that may influence transplantation outcome, including non-classical HLA molecules, such as MIC, and their receptors. KIR-related genes such as LILR are also polymorphic and will be of interest in the future.
What advice would you give to other researchers or clinicians interested in genetics of immune receptors, and how can they get involved in this field?
I would start by talking to the local experts in a tissue typing lab. There are excellent international societies that hold annual meetings, such as the European Federation for Immunogenetics (EFI) and American Society for Histocompatibility and Immunogenetics ASHI. Most developed nations have their own societies, including the Briish Society for Histocompatibility and Immunogenetics (BSHI).
Lastly, could you share any recent or upcoming developments in KIR that you find particularly exciting or promising in your research field?
The function of the conserved but polymorphic KIR3DL3 protein has been mysterious as it does not appear to interact with any HLA molecules. Recently it has been shown to be expressed in gd and CD8 T cells in the lungs and digestive tract rather than NK cells in blood. KIR3DL3 appears to interact with a B7 family ligand, HHLA2, making it a target for cancer therapy as an immune checkpoint.