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QnAswithMaxD.CooperandJacquesF.A.P.Miller QNAS

Brian Doctrow, Science Writer

Anyone who has ever contracted chicken pox can thank the adaptive for future pro- tection against the disease. It is also thanks to this system that prevent diseases. The provides organisms with a memory of past , enabling the body to quickly kill returning infections before they can do significant damage. Immunologists Jacques F. A. P. Miller and Max D. Cooper determined that adaptive requires 2 distinct cell types that perform comple- mentary functions. Miller’s findings, published in the early 1960s in Lancet (1) and Proceedings of the Royal Society (2), showed that the ability to distinguish one’s own cells from foreign cells, a key feature of the adap- tive immune system, depends on , now known as T cells, matured in an called the thy- mus. Subsequently, Cooper reported in Nature (3) that Max Dale Cooper. Image courtesy of Georgia Research production depends on a separate set of Alliance/Billy Howard. lymphocytes, dubbed B cells. The division of labor between T and B cells is a fundamental organizing principle of the adaptive immune system, the discov- did cancer research. I started working on leukemia and ery of which laid the groundwork for modern immu- this gave me an interest in lymphocytes. nology and made possible many subsequent medical advances, including produc- Cooper: I became interested through patients that I tion, development, and checkpoint inhibi- was taking care of: Children that had deficient immune tion therapies for cancer. In recognition of their capabilities and were susceptible to infections. Some of ’ discoveries, Miller and Cooper, both members of them couldn t defend themselves against a simple fe- the National Academy of Sciences, received the ver blister, a herpes simplex . It spread quickly and 2019 Albert Lasker Basic Medical Research Award. killed them. Others would have repeated bacterial infec- PNAS spoke with both researchers to commemo- tions. It was clear that if we were going to be able to rate the occasion. diagnose them more precisely and have any chance of understanding the pathogenesis of these deficiencies, PNAS: How did each of you get involved in studying and if we were going to be able to treat them, then we the immune system? needed to know more about how the immune system developed and functioned. Miller: I was interested in doing medical research from an early age, because my sister died of tuberculosis a PNAS: What was known about the at the time few years before streptomycin, and I got very curious you began your work? as to why some people get some diseases and others don’t. Also, because I was a child during the Second Miller: The thymus was [then] considered to be a World War and I did not have any for killing useless organ. Thymectomy, or removal of the thy- people, I decided I’d rather do surgery and patch them mus, from adult mice was not associated with any up instead. After my medical training, I got a fellowship defects. Immunologists thought it was a graveyard for to take me to the United Kingdom, in London, where I dying lymphocytes.

Published under the PNAS license.

www.pnas.org/cgi/doi/10.1073/pnas.1920087116 PNAS Latest Articles | 1of3 Downloaded by guest on October 1, 2021 PNAS: Meanwhile, Dr. Cooper, you were studying a lymphoid organ unique to birds, the bursa of Fabricius. As someone interested in research with clinical appli- cations, why did you decide to study an organ that only exists in birds?

Cooper: I was interested in a group of children who had an inherited disease called Wiskott–Aldrich syn- drome. At that time, the general idea was that the thy- mus generated small lymphocytes, as shown in Jacques Miller’s experiments, some of which became plasma cells, which by that point were known to make anti- bodies. Wiskott–Aldrich children had few lymphocytes, but lots of plasma cells and high levels of , which didn’t fit well with the single-lineage idea. Bruce Jacques F. A. P. Miller. Image courtesy of © 2019 The Walter and Eliza Hall Institute of Medical Research. Glick, a graduate student at Ohio State University back in the 1950s, and his colleagues showed that bursec- tomized chicks [whose bursae had been removed] were PNAS: How did you figure out that the thymus was in defective in making antibodies. It then became a ques- fact important for immune function? tion of whether the thymus and the bursa did the same thing or did different things. That was what triggered Miller: For my work on mouse leukemia, I had to take me to go back and revisit the avian model. out the thymus from newborn mice, which had not been done before. The neonatally thymectomized PNAS: Your key experimental innovation was irradiating mice were highly susceptible to , and they bursectomized and thymectomized chicks, to get rid of usually started wasting and being very sick about any immune cells that might have developed before the 4 months of age. When they died, I opened them up chicks hatched. What happened to these chicks? and found that they had very few lymphocytes, in contrast to mice that had been thymectomized as Cooper: Bursectomized and irradiated chicks, after adults. I knew that lymphocytes had been implicated recovery from the radiation—their thymus was normal, in immune responses, so I tested their immune their thymus-dependent small population responses by putting on foreign grafts, which and all of their cell-mediated immune functions were should normally be rejected. Incredibly, the foreign intact. But the birds no longer made plasma cells or skin grafts were not rejected. They grew luxuriant tufts antibodies, whereas thymectomy and irradiation gave of hair. You had 4 different types of skin graft on each the reverse pattern. So that allowed us to draw a pro- mouse, and even rat skin grafts were not rejected. And visional map of how the immune system developed that was spectacular. along these 2 lines.

PNAS: And then you transplanted a foreign thymus PNAS: Humans and other mammals do not have a into a host that had had its thymus removed. What did bursa but still produce B cells. How did you figure out you observe? where B cells originated in species other than birds?

Miller: The foreign thymus graft of course would not Cooper: The most telling experiments came during a be rejected because neonatally thymectomized mice sabbatical in England, at University College London, can’t reject foreign tissues, but the foreign thymus where I was working with John Owen and Martin Raff, graft would restore the capacity to produce immune using a method designed by John Owen to grow fetal responses, except to itself. In other words, skin from in culture. If we put fetal liver in culture before the same strain as the foreign thymus graft would be there were any B lymphocytes, cultured them for tolerated while skin from other strains would be several days, and then looked again, we could find B rejected. cells. So they’d been generated in that tissue. Those results (4), together with experiments done by others, PNAS: So why does thymus removal not cause suggested that B cells were generated in hematopoi- immune problems in adults? etic tissues: Fetal liver and marrow.

Miller: The thymus is putting out most of its cells from PNAS: More recently, you have shown that T-like cells before birth until the age of 3 years in humans, and and B-like cells are also found in jawless , maybe 7 or 8 months in mice. Most of the lymphocytes lampreys, and (5). What does this imply about that we need have already been made in early life and immune system evolution? they have a long lifespan. They recirculate and are ready to attack invaders. So you could say that the Cooper: This founding principle for the immune system thymus has done its job by about 3 or 4 years of age of having T- and B-like cells for adaptive immunity in humans. seems to be an old invention, one that evolved in

2of3 | www.pnas.org/cgi/doi/10.1073/pnas.1920087116 Doctrow Downloaded by guest on October 1, 2021 a common ancestor of both jawed and jawless Miller: At first I was criticized because people didn’t vertebrates—it’s thought—more than 500 million believe in T cells and their function, but I persevered. years ago. However, one of the most surprising things So I think one of the lessons to learn is to be patient, we’ve found is that jawless vertebrates don’tuse because it takes a long time to get results. Second is immunoglobulin segments to recombine and that serendipity is very important in medical research, generate diversity and make their receptors and anti- because a lot of great discoveries have been made bodies. They use leucine-rich repeat to gen- from serendipity. erate what appears to be an equally diverse repertoire of receptors for their T- and B-like cells Cooper: Sometimes you hear people saying that and antibodies. we basically know everything, it’s just a matter of put- ting it all together. I think that’s totally wrong. Every PNAS: Based on your foundational experience, what time we think we know everything, it turns out it’s lessons do either of you have for the next generation either wrong or incomplete, and there’slotsleft of immunologists? to learn.

1 J. F. A. P. Miller, Immunological function of the thymus. Lancet 2, 748–749 (1961). 2 J. F. A. P. Miller, Effect of neonatal thymectomy on the immunological responsiveness of the mouse. Proc. Roy. Soc. 156, 410–428 (1962). 3 M. D. Cooper, R. D. A. Peterson, R. A. Good, Delineation of the thymic and bursal lymphoid systems in the chicken. Nature 205, 143– 146 (1965). 4 J. J. T. Owen, M. D. Cooper, M. C. Raff, In vitro generation of B lymphocytes in mouse foetal liver, a mammalian ‘bursa equivalent’. Nature 249, 361–363 (1974). 5 Z. Pancer et al., Somatic diversification of variable lymphocyte receptors in the agnathan sea . Nature 430, 174–180 (2004).

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