Early on in the COVID-19 pandemic, Dr. Jennifer Lund and her colleagues at Fred Hutchinson Cancer Research Center set out to study how the human immune system reacts to this new coronavirus.
They began seeking what they call the “immune signature” in blood samples of patients who were seriously ill with COVID-19. The hope was to find a telltale pattern in how different components of the immune system react to the coronavirus and then compare that signature to those of influenza and RSV, two common, often harmful respiratory viruses.
The immune signature looked very much the same for all three viruses. But in the seriously ill COVID-19 patients, one thing leapt out: Within the mix of immune cells responding to that virus, there was a jump in the percentage of T-regs, or regulatory T cells.
Lund and her laboratory team specialize in T-regs. This was right in their wheelhouse.
Published in November in the journal Science Advances, the surprise findings are further evidence that T-regs, comparatively little-understood types of white blood cells in our immune system, have an outsized and underappreciated role maintaining health and fighting disease.
“T-regs are really important for achieving a kind of balance, for getting a good enough immune response against infection, but without causing so much damage to the host that they die,” Lund said. “That just really excites me. Mediating this balance of immune responsiveness is applicable to so many different diseases.”
The COVID-19 research, co-led by Lund and her Hutch colleague Dr. Martin Prlic, was funded by the National Institute of Allergy and Infectious Diseases.
Under a microscope, T-regs look no different than any other T cell. They are round and covered with a disheveled fluff of tiny protein receptors. Scientists have learned to distinguish them through high-speed cell-sorting machines that use molecular-scale fluorescent tags, pinned to those receptors, to identify and separate different varieties.
As a pivot point that may determine whether to turn immune responses up or down, T-regs are a tantalizing target for scientists. They are eager to deconstruct the complex systems that maintain immune system balance and protect us from microbial threats and cancer. What we learn about how these biological systems work can inform the development of vaccines and drugs that mimic their functions, to boost our immune defenses against viruses and tamp down autoimmune and allergic overreactions.
Ever since Lund joined Fred Hutch is 2009, her lab has been studying the complex ways that T-regs contribute to immunity to several viral infections, including HIV, West Nile Virus, Zika and herpes.
In fact, it all started with herpes.
— Fred Hutch immunologist Dr. Jennifer Lund
Lund's scientific career took off in 2008, when she was a postdoctoral researcher in the University of Washington lab of Dr. Alexander Rudensky, now chair of the immunology program at New York’s Sloan Kettering Institute. Lund set out to determine if depleting T-regs in herpes-infected mice might unleash a strong inflammatory response that could finally clear out the famously persistent herpes simplex type 2 virus.
To everyone’s surprise, the mice free of T-regs quickly died of an uncontrolled herpes infection. In the absence of regulatory T cells, other types of T cells, which move in to eliminate infected cells, seemed to be standing down. The results showed that, at least in the case of herpes, T-regs must have been promoting the immune response they were thought to suppress.
Lund was lead author of the paper, published in Science in 2008, a seminal study that made T-regs much more interesting, and puzzling.
“It was just an unexpected finding in the field,” Lund said. “That paper kind of set the stage for all the work I’ve done thereafter.”
Previously, T-regs had been known for their calming effects on other, more celebrated T cells. They could prevent those aggressive T cell defenders from mistakenly, like an out-of-control mob, attacking its own healthy tissues. Lack of T-regs has been implicated in autoimmune diseases such as eczema and diabetes.
“T-regs are mostly recognized for their role in preventing autoimmunity, but clearly they’re doing something as well in the context of infection,” Lund said. “And now we have shown in many different mouse models of different infections — and also in humans — that they do different things at different times and in different places. So, there’s just so much exciting work to be done.”
The normal function of most T cells is an aggressive one: to seek out tissues that have been infected by viruses or show signs of cancer, and either mark them for death by other immune cells or kill them directly. These T-cell weapons include CD4 helper cells, which are so essential that, when HIV targets and wipes them out, a person becomes vulnerable to lethal infections and cancers — in other words, they develop AIDS.
T-regs in fact are a subtype of CD4 T cells. In the human body, regulatory T cells account for only about 2% of all white blood cells and about 10% of all CD4s. Yet in areas where our bodies have lots of interaction with the outside world — such as in the mucosal tissues that line the gut — they comprise 20% or more of the local complement of CD4 T cells.
Like all T cells, T-regs come in a wide variety of flavors, and the work they do — whether quieting down inflammation or ramping it up — has a lot to do with which receptors they carry. Their task is also defined by the chemical chatter they have with other cells in their environment. It is a language of molecular communication among immune cells — commands, for example, to activate, rest, attack, retreat, attract, repel, multiply or die — that scientists are very keen to decode.
So, when Lund and other scientists are exploring the immune signature of viral infection, they are not just counting T-regs, T cells and other components of the immune system. They are also logging long lists of chemical signals provoked by the interaction of cells when they encounter a threat.
In the recent study of the immune signature created by COVID-19, Lund and her colleagues relied on a complex computer algorithm. It evaluated populations of dozens of different immune cell types — distinguished by different receptors — and traces of 71 different kinds of soluble, chemical signals. This mix of cells and signals together forms that signature of the immune response to the coronavirus, which can be compared to the patterns of immune responses to other viruses.
While T-regs are best known for tamping down the immune system, Lund’s herpes research had already proven that this is not always the case. So, it is unclear what this telltale COVID-19 signature means. The next step is to find out whether this increase in regulatory T cell levels is good or bad for patients.
In the case of COVID-19, Lund noted that the build-up of T-regs was found in circulating blood, while studies by other researchers have shown deficient levels of these cells in the airways itself, which is battling tissue-damaging inflammation. Lund hypothesizes that, in cases of severe COVID-19, T-regs are not functioning properly in lung mucosal tissue, and that a lack of T-regs tamping down the raging response of T cells to the infection could be contributing to disease.
“Maybe they’re not getting to the place where you need them,” Lund said. Current research by the group is looking to confirm that model.
Her lab is also trying to unravel the puzzle of T-regs in HIV infection. In a long-running study of women in Kenya, researchers are trying to understand the role of immune suppressing cells in the mucosa of the female reproductive tract. While it would seem that a strong immune response against HIV would be beneficial — to prevent infections — HIV is a disease that specifically targets CD4 T cells and dendritic cells, both of which are components of our immune systems. In a sense, the activated T cells are serving themselves up, providing rich targets for HIV infection. The researchers therefore are trying to learn whether T-reg suppression of the immune response might actually be protective against infection.
The study of mucosal tissues, the borderlines where our bodies interact most directly with the environment, is a major focus of the Lund lab. Dr. Brianna Traxinger, who has just completed her Ph.D. studies in T-cell immunology there, is lead author of a recent paper giving a broad overview of the role of T-regs that reside, not in the bloodstream, but within mucosal tissue sites including the lung, gut and vagina. Her work has focused on the female reproductive tract.
“It is both the entry site for sexually transmitted infections and also the home to beneficial bacteria. The vaginal immune environment must simultaneously balance immunity and tolerance, fighting off deleterious microbes while allowing healthy ones to thrive,” Traxinger said.
T-regs also may be essential instruments for orchestrating the potential clash of immune systems between fetus and mother.
“During pregnancy, the immune system must not react to the foreign proteins expressed by the fetus,” she said. “We think T-regs are likely in charge of fine-tuning the complex immune responses in the female reproductive tract, which requires careful immunoregulation.”
The lung is also a sensitive zone where thin layers of mucosal tissue guard the bloodstream from airborne viruses, bacteria and allergens. But T-regs may shoulder their most difficult task in mucosal tissue of the digestive tract, where they must help to keep out invasive pathogens and welcome healthy gut biota that metabolize foods, while also maintaining tolerance to foods that might provoke an allergic reaction.
Sorting out these complexities is the kind of work that immunologists like Lund and Traxinger love.
Looking ahead, Lund said that she would like to do more research on human immunology, as the mouse work she has done for years has limits in applicability to people.
“Since I started at Fred Hutch, we’ve increasingly been doing more human immunology, and I’d love to continue in that direction. A lot of our papers now have mouse and human data, and while it is great to ask these mechanistic questions in mice, we ultimately want our findings to be relevant to human health,” she said.
“Because in the end, we are not trying to cure mice of herpes.”
Sabin Russell is a staff writer at Fred Hutchinson Cancer Research Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT, and a freelance writer for the New York Times and Health Affairs. Reach him at firstname.lastname@example.org.
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