Rewriting the Rules of Immunity

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This story is from the 2026 issue of Discoveries, a UC San Diego Health Sciences magazine.

It never entered his mind … not really.

While blissfully hiking his way through the snow-covered wilds of Montana last October, it didn’t occur to Fred Ramsdell, ’83, PhD, or his wife and hiking companion, Laura O’Neill, that he was being considered for the Nobel Prize.

A scientific advisor with Sonoma Biotherapeutics in San Francisco, Ramsdell had already won the Crafoord Prize in 2017 for his role in unraveling how immune systems are kept in check from attacking their hosts. He figured the prestigious nature of the Crafoord Prize would be the pinnacle of his discovery’s recognition. “I never thought about it again after that,” said Ramsdell. “It just never crossed my mind. I’m still in a little bit of a state of shock, to be honest.”

When he got the call from the Nobel Prize committee, Ramsdell was well off the grid. The official notification of his selection as a Nobel Prize winner in physiology or medicine didn’t reach him until he emerged from the backcountry at the small town of Livingston, Montana. Since that day, his life has not been the same.

Discoveries magazine< spoke with Ramsdell, who received his undergraduate degree in biochemistry and cell biology from UC San Diego and his PhD from UCLA, during a November 2025 interview, shortly before he attended the Nobel Prize ceremony.

Fred Ramsdell ’83, PhD: UC San Diego is where I actually fell in love with immunology. I took a course from a professor there named Dick Dutton, who’s a famous immunologist. I got hooked right away. I was amazed at how important the immune system is and yet how little our knowledge of it was at that time. This was the early ’80s, and we were just developing the tools that have opened up so much since then. Our understanding was really rudimentary at that point, but it was clearly important for everything.

One of the things about the immune system is its focus, as most people think, to keep us well from pathogens — viruses, bacteria — and prevent us from getting sick. When we get sick, we develop an immune response to that. We don’t get sick as bad the second time. It’s gotten very good at that over millions of years of evolution. However, it can also recognize our own tissues. That’s why some people get arthritis, Crohn’s disease, multiple sclerosis and a number of other diseases. The immune system has a built-in system so that most of us don’t come down with those diseases.

One of the things that controls that system is a small set of cells within the immune system called regulatory T (Treg) cells. We didn’t know about these back in the ’80s, but in the ’90s one of my co-laureates, Shimon Sakaguchi, described these cells in mice. They’re a small set of lymphocytes (white blood cells that serve the immune system) that are in our blood, inside all our tissue, that dampen responses to our own tissues.

They have other functions, such as helping to repair tissues following damage. Shimon described these cells in mice and their ability to control the immune response, but they weren’t characterized terribly well. We didn’t have a molecular signature for these cells. We didn’t really understand how they worked. When I started my own career, I was very interested in trying to figure out how the immune system regulates itself because autoimmune disease is clearly a failure of that regulation.

We focused on a mouse that was made back during the Manhattan Project — it had rampant autoimmune disease. It had all of the autoimmune diseases you could think of. This was a complete failure of that regulatory process.

Stephen Hedrick, PhD, Distinguished Professor Emeritus, Department of Molecular Biology: You never know where huge breakthroughs are going to come from. Who would have known that this mouse, a strain that was developed in Tennessee in the 1940s, would lead to an understanding of a fundamental aspect of the immune system? The part of immunology Fred Ramsdell started studying turns out to be absolutely critical. I don’t know whether Fred anticipated how important this would be, but certainly the insight to go after the gene in the scurfy mutant mouse strain was brilliant.

Li-Fan Lu, PhD, professor, Department of Molecular Biology: The scurfy mouse was developed by the Oak Ridge National Laboratory that was established back in 1943 to study radiation exposure during a nuclear war. Fred, as an immunologist, worked with Mary Brunkow, who is a geneticist, in the same company, and they set out a kind of forward-genetic approach to figure out which region contained the mutation responsible for the scurfy phenotype in mice. They didn’t have a formal setup for this. They had hundreds of cages of mice in a janitorial room and kept breeding. Eventually, they shortened the region to 500 kilobase that have the mutation responsible, and within those 500 they focused on 20 open reading frames. Eleven were either known genes or novel genes within a known gene family, and nine were novel expressed sequence tags (ESTs). They failed 19 times but finally found the Foxp3 gene on the very last one. It’s a good story of resilience that we should tell all young scientists.

Ramsdell: Foxp3, it turns out, is only expressed in a subset of cells that Shimon Sakaguchi described as regulatory cells. Mary Brunkow cloned the gene, and we subsequently showed that the same gene existed in humans …We now had a molecular characterization for the cells, and we could much more readily explore the function and the lack of function of these cells in autoimmune patients. And that’s what the (Nobel Prize) award is for.

More important than the award is now understanding the regulatory processes, or at least dominant regulatory process, in people that control autoimmune conditions. We postulated back in the year 2000 that if you could give a whole bunch of these cells to autoimmune patients, you might be able to control their disease. The big problem was that no one would do cell therapy back in those days. But if you flash forward 15 years, we’ve learned a lot. Now you can actually do those programs. People are putting these cells into patients and trying to see if we can cure disease. There are numerous companies doing it. I actually helped start one of them.

David Goeddel ’72, PhD, a widely recognized biotechnology industry leader: It’s an incredible achievement that Fred Ramsdell did this work in the biotech industry. Too often, so-called “basic” research is not supported in biotech, especially in recent years. For the public, the implications are many. This work will result in therapies for auto-immune diseases as well as improved organ transplants. For science, a whole new field of study has been established that opens up opportunities for many scientists to leverage these discoveries in their own work.

Hedrick: Some cancer therapy treatments are thought to work by inactivating regulatory T cells. Allowing the immune system to more fully realize its capability certainly involves blocking regulatory T cells. Autoimmunity is another opportunity. Americans experience profound autoimmunity in some form, including rheumatoid arthritis and all kinds of other things. So if you understand that one of the defects that occur in people with autoimmune disease is an absence or diminished activity of regulatory T cells, and how that might be worked as a treatment, it’s going to be important.

Rana McKay, MD, medical oncologist, UC San Diego Health; clinical professor, UC San Diego School of Medicine: Tregs normally serve as the immune system’s brakes. They are there to basically prevent auto-immunity by suppressing overactive immune responses. In cancer, the same mechanism that is otherwise protective is hijacked by tumors. Cancers can recruit and expand Tregs within the tumor microenvironment to almost create an immunosuppressive protective shield, and this allows them to grow unchecked. With the Tregs in the microenvironment, the tumor is blind to the immune system. So the understanding of this biology opens up the door for therapeutic strategies targeted at removing Tregs from the microenvironment.

Lu: You can think of regulatory T cells as a police force, but even within the police force there are specialized tasks. In tumors we know that regulatory T cells are bad; they shut down the anti-tumor immune response. But the problem is that you cannot get rid of them. Even if you could get rid of them, you could enhance the anti-tumor response that helps you get rid of the tumor, but then you could get fatal autoimmunity.

McKay: It’s worth highlighting the critical importance of bench-to-bedside medicine. This discovery shows how basic science discoveries and immunology can really be translated into potentially lifesaving cancer treatments. This really highlights how important it is to support the bidirectional flow between bench and bedside — that circular exchange is really important.

UC San Diego is uniquely positioned at the intersection of basic biology and clinical oncology research, and we are building the kind of environment within Moores Cancer Center at UC San Diego Health that allows us to directly translate our basic science and translational discoveries in the clinic. The center is actively running clinical trials that leverage these types of immunological insights. Clinical trials basically offer the treatments of tomorrow today to our patients.

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