Understanding the Immune System to Predict, Prevent, and Treat Diseases

The immune system consists of 1.8 trillion cells distributed across every tissue of the human body. And yet, size alone cannot capture how complex the system really is.

“The immune system interfaces with all of physiology,” says John S. Tsang, PhD, MMath, Anthony N. Brady Professor of Immunobiology at Yale School of Medicine (YSM). “It is implicated in almost everything, from health to disease.”

At YSM, researchers across numerous departments are working to decode the immune system. Basic scientists work alongside clinical researchers to uncover how the immune system works on a fundamental level and translate those findings to prevention and treatment for disease. Their work is ushering in a future where the immune system itself can be a measure of health, a predictor of disease, and the mechanism by which illness is treated.

“If you could really understand how it works and measure it well, it provides a window into all of these conditions,” says Tsang. “As a system evolved to maintain health, the immune system senses what goes on around the body. We’re just beginning to develop the understanding and technologies to listen.”

In the early 2000s, Richard Flavell, PhD, Sterling Professor of Immunobiology, looked across his department, where he was then chair, and saw a gap. Physician-scientists who saw patients returned to their laboratories to study their patients’ diseases in mouse models. And Flavell thought that was a disconnect. With support from the YSM dean at the time, Flavell recruited Jordan Pober, MD, PhD, Bayer Professor of Translational Medicine, and Joseph Craft, MD, Paul B. Beeson Professor of Medicine (Rheumatology), to help design a program to bridge this gap between human and animal research.

“We wanted to blur the lines,” says Pober, “and not distinguish what was going on between the Department of Immunobiology and what was going on in the clinic.”

Together, in 2006, they created the Human and Translational Immunology Program (HTIP). The program’s goal is to accelerate the application of new discoveries in the field of immunobiology to the treatment of human diseases. It does this by bringing together basic and clinical scientists with shared interests and providing resources to support collaborative research.

HTIP’s first recruit was Kevan Herold, MD, C.N.H. Long Professor of Immunobiology and professor of medicine (endocrinology). What drew Herold to the immune system was type 1 diabetes, in which the immune system destroys insulin-producing cells. Herold observed that some insulin-producing beta cells were being destroyed years before a patient presented clinical symptoms. In other words, the immune system was broadcasting a signal long before disease detection.

Now, his lab studies how to intercept that signal, developing therapies not just to treat type 1 diabetes, but to interrupt the immune process driving it. In 2019, his team conducted a clinical trial where they demonstrated that teplizumab, an antibody developed through their work, could delay the onset of diabetes. In 2022, it became the first drug approved by the U.S. Food and Drug Administration (FDA) to change the course of type 1 diabetes since the disease’s discovery.

“HTIP provided a good intellectual home for the type of work I was doing," says Herold, who is now program director of HTIP. "There is very close collaboration across all of the departments involved.”

HTIP’s members hail from over two dozen departments and sections. It’s a hub where researchers with complementary interests can apply their different methods and perspectives to a common problem, deepening understanding overall and accelerating treatment development.

Carrie L. Lucas, PhD, associate professor of immunobiology, is part of that hub. The Lucas Lab focuses on genetic diseases. “Think of the immune responsiveness across the human population as a bell curve,” says Lucas, who is also associate director of HTIP. “At one end are individuals whose immune systems are dangerously underactive and at the other are those whose immune systems are pathologically overactive.”

Her team studies both ends, and they believe their findings may provide insights for those in the middle as well.

One focus of Lucas’ research is a signaling molecule called PI3K (phosphoinositide 3-kinase). Her team has found that both overactive and underactive PI3K lead to immunodeficiency syndromes. For the former, they uncovered genetic mutations that underlie the condition, and that work led to clinical trials for a drug that targets inhibitors of the signaling molecule, which has since been approved by the FDA.

Her lab is also studying an autoinflammatory condition in males that the lab discovered and named DEX (deficiency in ELF4, X-linked).

“For us, it is the single-cell type approach that is opening new doors for understanding human immunity,” Lucas says. “By identifying these causal genes and pathways we are uncovering fundamental biology that is relevant to the whole population.”

Pober, who served as director of HTIP for two decades, says this perspective has now spread throughout the scientific community. “Over time, what became apparent to much of the clinical world is just how critical the immune system is to almost every area of medicine,” he says.

It was that realization that led to another YSM program—the Center for Systems and Engineering Immunology (CSEI).

For Tsang, variation across individuals has driven much of his research. For example, a malaria vaccine developed in North America shows 95% efficacy in clinical trials. When used in the endemic regions of sub-Saharan Africa—the very population that needs it most—its efficacy drops to 30%. Two patients of similar age and sex contract SARS-CoV-2; one is hospitalized and critically ill, the other feels no symptoms. In oncology, checkpoint inhibitor therapies—a type of immunotherapy used to boost the body’s proteins for better immune attack—produce dramatic immune responses in 30-40% of patients. The rest do not respond.

For Tsang, these inconsistencies across three domains of medicine led to one underlying question: Why do different people respond so differently to the same vaccine, the same virus, or the same drug?

"Differences among individuals and populations—it's actually an advantage, not a burden,” says Tsang. “You need those differences in order to have the power to build models and start asking why."

That conviction became the founding philosophy of CSEI, launched in 2022 and directed by Tsang. CSEI is a home for scientists across Yale School of Medicine, Yale Engineering, and the Faculty of Arts and Sciences. The center is united by a mission to build quantitative and predictive understandings of the immune system, and it has attracted new researchers to YSM.

Armita Nourmohammad, PhD, associate professor of immunobiology at YSM and of biomedical engineering at Yale Engineering, joined the YSM faculty in January and is currently the associate director of theoretical sciences at CSEI. She says one of the reasons she came to Yale was CSEI.

“The vision there is really to build this collaborative environment where you have experimentalists and theorists working together, and the whole is larger than the sum of its parts,” she says. “That was very important to me.”

Hao Yuan Kueh, PhD, associate professor of immunobiology, joined YSM in September 2025. “The key aspect of the center, and this is what drew me here, is that we break down barriers between immunologists, engineers, physicists, computer scientists, and the idea is to get people at all levels—faculty, trainees, graduate students, postdocs—talking to each other and exchanging ideas,” says Kueh. “It creates an environment where creative, out-of-the-box ideas are encouraged.”

Hattie Chung, PhD, assistant professor of medicine (cardiology) and a member of CSEI, studies complex tissue environments, and she sees them not as collections of cells but as circuits in which constant interactions form the basis of health and disease.

"When someone in ballet is standing on their points," she says, "it looks like they are standing still. But standing still takes hundreds of muscles interacting with each other to maintain that balance. Your system is internally not static to maintain that static-looking point.”

The immune system, she says, is not that different. It is not a fixed or mappable structure; rather it is dynamic—constantly remodeling, sensing, adapting, and responding.

“Understanding cell circuits and cellular interactions and how they maintain homeostasis is a key interest of my lab’s research,” Chung says. “Our goal is to advance predictive biology for tissues.”

Her lab is developing novel computational and experimental tools that will help them define the “grammar” of cellular interactions within tissues. With that in hand, they can then begin to uncover the mechanisms that drive tissue resilience or failure and how they might be targeted to treat disease.

The lab is currently applying that work to study ovarian aging and cardiovascular diseases, with the ultimate goal of understanding how tissues maintain homeostasis, how they change with age, and how they recover from injury within the context of disease. By understanding the cellular and molecular changes that drive tissue function, says Chung, they can uncover fundamental principles of tissue circuitry and use them to identify new therapeutic targets.

Andrew James Martins, PhD, assistant professor of immunobiology and associate director for technology at CSEI, is interested in individual immune cells and how they transition into different states, such as reproduction vs. dormancy.

“We are trying to understand the fundamental nature of cell state transition in human immune cells, which is traditionally challenging because you can't really track these cells in human tissue in vivo very easily,” he says. “But if we can take the cells from the blood and put them in different culture models, we can observe how they behave.”

This, he says, enables them to perturb immune cells with different treatments, ranging from drugs to different immune stimulatory treatments, to understand the cells better.

“We want to cast as broad a net as possible," he says, "to capture the features of the immune system.” This would require moving from hundreds of samples—the typical scale of a lab—to thousands, across diverse populations and disease contexts. “And that will be really informative for pushing forward the goal of predictive immunology,” Martins says.

CSEI is working to scale research in just that way as part of two large collaborations. The center rests on two pillars. One is conceptual and methodological, in which the researchers are building tools to measure the immune system at a depth not previously attempted. The other pillar focuses on physiology—how to integrate those measurements not in isolation, but across all diseases and populations.

As part of the second pillar, CSEI is a member of the Human Immunome Project, a global partnership network coordinated by CSEI that aims to study immune responses in individuals around the world, over time, in a standardized way. That, Tsang says, will allow comparison across populations.

Additionally, YSM is a key member of Biohub New York, a collaboration that also includes Rockefeller University and Columbia University and has a mission to “cure or prevent all disease.”

Several YSM researchers are part of Biohub’s Immune Cell Reprogramming Program, which was born from an idea that originated from Tsang when he was working on founding the CSEI. The project’s goal is to engineer human immune cells to become tiny sentinels, sensing early signs of disease as they travel throughout the body and delivering information. “We need to push from tinkering to predictive and systematic engineering,” says Tsang.

Once successful, it would mean immune cells could be harnessed for living diagnostics, says Tsang, who is the Yale lead for Biohub New York and serves on its steering committee.

"That's the dream," he says. "Immune cells that don't just respond to disease—but seek it out, report back, and act. Some pieces will come sooner than others, but we're moving faster than anyone expected."