16 Nov 2020
Issue #33: T cell Recognition
Setting it Straight - Issue #33
Written by Nobel Laureate Professor Peter Doherty
Last week’s essay was a bit tortuous, but I wanted to show how we discovered both the true nature of T cell-mediated immunity and the reason why we have a transplantation system. And I was also echoing the point made by Isaac Newton (of apple/gravity fame) back in the 17th century that, as scientists, we are part of a continuum. In Newton’s words, “If I have seen further it is by standing on ye shoulders of giants”. This is in a letter to his hated competitor Robert Hooke (Hooke’s Law) who, partly due to a curvature of the spine, was very short in stature: it may not have been a totally amiable observation!
In our case, the ‘giants’ were the mouse transplantation geneticists who, over decades, produced the massive resource of genetically defined mice that, in just two years, allowed us to unpick our chance discovery. We remain enormously grateful, though it took some of them a long time to acknowledge that two noisy young unknowns working with viruses had solved their problem. Question: Why do we have a transplant system? Answer: Your major histocompatibility complex (MHC) should be called the ‘self-surveillance complex’ (SSC).
Sir Macfarlane Burnet, a virologist who loved to speculate, observed that transplantation differences would stop tumours transferring from one person to another. Though that cannot be the main reason, it does describe the situation for the very inbred Tasmanian Devil, which transmits a horrible tumour (a Shwannoma) by biting. Another theory, by Wistar Institute rat geneticist Joy Palm, argued that the MHC difference between mother and conceptus might work to promote placental size and foetal viability. Basically, nobody was thinking in terms of ‘immune surveillance of self’.
We summarised the theoretical implications of our experiments in a short ‘Hypothesis’ article (The Lancet 305 (7922), 1406-1409, 1975), which proposed that killer T cells use a single T cell receptor (TCR) to recognise ‘altered self’, defined loosely as some change in the cell-surface MHCI glycoprotein induced by the infecting virus. And we further speculated that the evolutionary pressure to maintain both several MHCI loci and the extreme polymorphism of the MHCI alleles (genes) represented a biological ‘insurance policy’ to ensure that no virus could fail to form a TCR-recognisable ‘altered self’. In other words, across a genetically diverse population, there would be no ‘holes in the immune repertoire’ that might allow a novel pathogen to avoid T cell-mediated immune control and wipe out the species in question. The latter is, in fact, most readily demonstrated for domestic chickens that have only a single MHCI locus (compared with three in us), so there is less ‘back-up’ if one response fails. A final suggestion was that TCR recognition by ‘helper’ T cells worked in the same way for the MHC class II molecules. Though it was impossible at that time to define the underlying molecular mechanisms, we were right on every point.
At that stage, the TCR was always described as ‘enigmatic’ (nobody knew what it was) and most researchers thought that killer T cells had two different receptors – one for a virus component (antigen) expressed on the surface of an infected cell and the other for the MHCI transplantation glycoprotein. As late as 1983, the predominant view was that the virus-specific TCR was an Ig heavy chain identical to that on an IgG molecule specific for the same viral protein. That made no sense to me. The fact that it was completely wrong just reflects the state of the technology back then, plus a certain amount of wishful thinking.
Between 1983 and 1985, Alain Townsend, an MD PhD student working with a great friend, Ita (Bridget) Askonas at the National Institute of Medical Research Mill Hill, London, established that our ‘altered self’ is a small viral peptide (8-12 amino acids) bound to a cell-surface MHCI glycoprotein. Next, Pamela Bjorkman, Don Wylie and Jack Strominger at Harvard showed by X-ray crystallography (structural biology) that there is a ‘smear’ (the peptide) in the MHCI groove. Completing the story, molecular biologists Mark Davis and Steve Hedrick at the National Institutes of Health used a novel subtractive hybridisation approach to discover the TCRβ gene. Other molecular analysis by Tak Mak (Toronto) and Susumu Tonegawa (MIT) strengthened these findings and found the TCRα that encodes the second half of the two-chain TCRαβ heterodimeric receptor. Finally, the year we were awarded the Nobel Prize (1996), Ian Wilson at the Scripps Institute, La Jolla, published the first image of a co-crystal showing a TCR bound to its complementary pMHCI ‘epitope’.
After we went our different ways in 1975, Rolf Zinkernagel and I continued to be good friends though we did not always agree scientifically, especially on immune memory, a major focus for me. Rolf was at the Scripps, then at the University of Zurich with long-term colleague, molecular biologist, Hans Hengartner. They both retired in 2008, and their former trainees hold key positions in Europe. I worked at the Wistar Institute, again at the ANU, at St Jude Children’s Research Institute (SJCRH) Memphis and, finally, the University of Melbourne.
Continuing with the immunobiology of virus infections in mice, I left LCM principally to Rolf and focused mainly on influenza and the complex murine γ-herpesvirus 68 (MHV68), which resembles Kaposi’s Sarcoma virus of humans. Through those years, I worked with many wonderful young colleagues. Australians who were with me in Memphis include Gabrielle Belz (Translational Research Institute, Brisbane) and Philip Stevenson (University of Queensland). Paul Thomas took over my laboratory at SJCRH, where he leads a very dynamic and diverse program focused on respiratory infections and, latterly, cancer.
Of the postdoctoral fellows who started our University of Melbourne laboratory from 2002, Katherine Kedzierska (Doherty Institute) and Steve Turner and Nicole LaGruta at Monash, lead major research efforts in human and mouse T cell immunology and molecular biology. Next generation trainees Misty Jenkins and Sophie Valkenburg have laboratories at the WEHI and the University of Hong Kong, respectively. It has been a great privilege and pleasure to keep such wonderful company through those years and now, in this time of COVID-19 at our great Melbourne Institute of Infection and Immunity. Science is a continuum. It’s about finding out and solving problems, not about glittering prizes, though that can happen!