The Rise and Fall...and Rise...of T Suppressors Part II

Continuing our look at the history of T suppressor cells and Tregs, we spoke with Dr. Douglas Green. Dr. Green was one of Dr. Gershon's graduate students and has first-hand knowledge of the excitement and troubles that came with T suppressor cell discovery.
Dr. Richard Gershon
Photo by the Journal of Immunology
  Dr. Douglas Green
Chair of Immunology, St. Jude's Research Hospital
Photo by St. Jude's Research Hospital
 
I worked with Dr. Gershon from 1978-1981 as a graduate student (receiving my Ph.D. in Dec. 1981). Following that time, I worked as a postdoctoral fellow until his death. My own project concerned a phenomenon we called "contrasuppression," mediated by T cells that rendered helper T cells resistant to suppression. The phenomenon was certainly interesting, although I'm sure that today we would reframe it in terms of cytokines that mediate the effect (while it would not be difficult to do that, my own research has moved well away from such issues, and it would be hard to justify in the context of my work--I'm sure that someday it will all be clear!).
There were a variety of issues that led to the demise of the suppressor T cell paradigm.  Most of all, the technology was phenomenological, lacking molecular basis--the field was in transition as molecular approaches came into use, and several phenomena tied to suppressor T cells did not yield to such analysis. Here are a few of the issues:
A) Antigen specific suppressor factors: During the 60s and 70s, the focus was entirely on the response of T cells to specific antigens. The B cell receptor had been identified based on characterization of soluble antibodies, and it was believed that any relevant effect of T cells had to be via a similar soluble receptor (that was antigen specific). There was very little interest in "factors" that were non-specific, such as cytokines (we now understand that these are fundamental to the functions of T cells). While there were studies that suggested that T cells make antigen-specific, soluble factors that mediate their functions, including suppression, these did not yield to protein or molecular analysis.  The field moved on, and there is no longer a "place" for such factors in our understanding. Do they exist? Possibly (maybe, probably ?), but we do not know how they would fit into our thinking if they do. We did make some progress in defining such factors in the 80s, but by then there was little interest in them, and I suspect that whatever we were studying was unique to the systems we used-- we simply don't have a way to fit them into a larger picture.
B) The characterization of "I-J": At the time suppressor cells were studied, the reagents we used (as well as the methods we employed) were very rudimentary. Part of what drove the idea that suppressor T cells are a unique, functional population depended on crude antibodies that defined them. Prominent among these was I-J, which was thought to be encoded among the genes for the class II MHC molecules. No such molecule was ever defined. This was a major blow to the field. That said, Ron Germaine at the NIH has pointed out that the studies that showed that there was no I-J were suspect, but ultimately I'm not sure this is relevant--we never identified I-J.
I-J was believed to be a T suppressor specific determinant...but it was found to not exist. I-J publications (red bars) for it quickly dropped off upon this discovery. T suppressors resurfaced as Tregs in the late 90s, and its publications (green bars) boomed as a result. Learn more here.
C) Defining the mechanism of suppression: This is often cited as part of why the field imploded, although I think it is interesting that we still do not really understand how Tregs work.
D) Failure to "clone" suppressor T cells: This is another, often cited (at the time) reason for the demise of suppressor cells. While we could generate clones of helper T cells and cytotoxic T cells, we could not generate long lived suppressor cells. Few use this approach today, and it wasn't much of a reason (If you're interested, I know why this failed in some cases-- at least one type of suppressor T cell, which we have fully characterized, dies upon the release of the immunosuppressive cytokine. I'm not sure there is much value in dredging this up-the characterized phenomenon was described in a paper in Immunity a few years ago, but we didn't have much interest in pushing the idea that this is how suppressor cells work--we've moved on to describe important phenomena in immune regulation that stand on their own).

Ultimately, I think that the reasons for the demise of suppressor T cells and their being replaced by Tregs was largely sociological. There was a cadre of politically powerful laboratories that dominated the field, and as the winds shifted towards molecular characterization of immunologic phenomena (which proved extremely powerful, scientifically) people working on other problems were happy to let suppressor cells "go away."  From the perspective of the history of science it is an interesting time, and the field has benefited from not worrying too much about what was right and what was wrong.
  Sadly, T suppressors were allowed to fade away.
Arrested Development, Netflix.
 
VERY much so. After Gershon died, a prominent immunologist came to the lab to "help" his trainees, and he told me flat out that I was, um, screwed (he used a more vulgar term). He suggested I find something else to do with my life, but not science. I ultimately took a position at the University of Alberta in Edmonton, and went back to my first principles. I had always wanted to study the immune system as a way to understand basic mechanisms of development, and I read extensively to try to get back to that goal. During my five years in Edmonton (I was promoted to Associate with Tenure and was up for full professor when I left--more on that below), I decided to try to understand what was happening during clonal deletion (also called negative selection) in T cell development, an idea that remains at the core of modern immunology and "self-nonself" discrimination. I reckoned that this had something to do with cell death, which was a very understudied area. I decided to work on it, and ultimately never looked back--today our laboratory is prominent in areas of cell survival and cell death.
Funny thing about that, though. As the field of cell death began to take off in the late 80s (and me along with it, if I can say that), I was offered a position (which I took) in San Diego at the La Jolla Institute for Allergy and Immunology. Kimishige Ishizaka was the director, and recruited me, NOT to work on cell death, but rather suppressor T cells and factors. But part of the deal was that I would work on what I wanted to, and my studies mainly focused on cell death and survival.
It may be worth noting that several very prominent immunologists started out in the study of suppressor T cells. Notable among them are Ron Germaine (NIH), Mark Greene (U. Penn.), Masaru Taniguchi (Chiba), and Vijay Kuchroo (Harvard). From Gershon's lab, in addition to me, Tom Ferguson (Wash. U.) is a leader in the study of the eye and vision (in fact, we recently published a paper together in Cell, which was terrific). Scott Durum (NIH, NCI), Reynold Verret (Savannah State U.), Pat Flood (who was at UNC Chapel Hill for many years but recently moved to, of all places, the University of Alberta), and the recently (sadly) deceased Yacov Ron (UMDNJ) all did well.
Having the community abandon your field of study can be a bit unnerving.
Scrubs, ABC Studios.
Sakaguchi's discovery really did lead to the characterization of Tregs. While I am sure that many of the phenomena Gershon studied were mediated by Tregs, the paradigm he had established would not have permitted the progress that Sakaguchi's finding ultimately did.  Still, there would be no field of Tregs if the labs of Steve Zeigler and Fred Ramsdell had not discovered the Foxp3 transcription factor and its role.  Prior to this, Tregs were a phenomenon no different from suppressor T cells.
Nice of him to say, but I'm not sure I agree. I loved Gershon's sense of fun and his deep intellectual interest in scientific problems, and I very clearly remember (and hold to) something he told me once: marathon runners have this thing called "the wall"--a point at which they simply cannot continue, and the real athletes push through it. To be a scientist (in his meaning of the word) you have to think until you hit the wall, and keep going. I try to do that. Sometimes maybe I do. One of my proudest moments in recent years came when I saw Charlie Janeway (a brilliant scientist and Gershon's colleague and friend) shortly before he died—he was ill but sharp, and he looked at me and said, "You did all right." Nice.
Even if your academic bubble pops, you can go on to be successful.
Tropic Thunder, DreamWorks Pictures.

To learn more about Tregs, check out our website here. If you have any comments on this story, leave us a message here.

If you missed part I of the Rise and Fall…and Rise of T Suppressors, catch the podcast here.

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