La Jolla Institute for Immunology (LJI) Postdoctoral Fellow Gurupreet Singh Sethi, Ph.D., thinks we may be able to rid the immune system of bad memories.
His research has revealed a small group of T cells hell-bent on remembering allergens for years after a person suffers an asthma attack. He’s hoping scientists can target these T cells to stop them from triggering asthma attacks ever again.
“We’re talking about the root cause of the disease—about helping people with severe asthma who don’t respond to current therapies,” says Sethi.
Over the past year, Sethi has made progress in understanding asthma thanks to research funding from LJI’s Tullie and Rickey Families SPARK Awards for Innovations in Immunology. The award led to the development of a mouse model for studying allergic asthma—and the discovery of this dangerous group of “memory” T cells.
Now Sethi has won additional funding from the SPARK program, which he plans to use to figure out which memory T cells in the allergic lungs are the worst of the worst. These mysterious cells can survive the asthma treatments and could be responsible for the reappearance of disease symptoms—a condition referred to as therapy-resistant asthma. “In the Croft lab recently, we replicated this clinical situation in a mouse mode,” says Sethi. “Now our plan is to uncover and understand these complex asthma settings and learn how to target these T cells.”
“We love what Gurupreet has done with asthma. We love the research he’s done so far and where it’s going,” says SPARK program founder Dave Rickey, who supported Sethi’s original SPARK project and reviewed his “progress pitch” for additional funding.
The urgent need for asthma answers
In his eight years as an asthma researcher, Sethi has seen many promising ideas come and go as researchers search for long-lasting asthma treatments. “I’ve observed a lot of progress in this time, but there are still a lot of gaps,” he says.
The leading asthma treatments don’t work for many patients. Their doctors can’t address the root cause of the disease, just the symptoms. “We are still talking about disease management,” says Sethi. “This is a bit frustrating for me. We’ve known about asthma and studied asthma for a long time, and we are still struggling to find a cure or even long-lasting relief for asthma patients.”
In 2020, the most recent year where we have CDC data, more than 25 million Americans (7 percent of the nation) were reportedly struggling with asthma. Four thousand one hundred and forty-five of these people died of the disease in 2020. Those most at risk for a fatal asthma attack were African American women.
A handful of terrible T cells
T cells normally help the body by stopping infections and zapping cancer cells into oblivion. After each battle, a small group of T cells sticks around to serve as “memory” T cells—ready to alert the body if an attacker ever returns.
For people with asthma, T cell memory turns into a big problem. Instead of reacting to pathogens, T cells in their lungs commit harmless molecules to memory: bits of dust mite proteins, cat dander, pollen, or mold spores, for example. When a person encounters those allergens again, their T cells mistakenly launch an all-out war, driving waves of inflammation and mucus production.
This rapid overreaction is an asthma attack.
In his first year as a SPARK winner, Sethi hunted down the memory T cells that survive in the lungs for years after an asthma attack. This is a rare subgroup of T cells. Some researchers refer to T cell subgroups as different “flavors” of T cells. In that analogy, these T cells are the curdled milk.
Using a technique called single-cell RNA sequencing, Sethi explored these rare cells and uncovered their genetic profiles. His research in mice revealed that the pool of bad memory T cells is made up of around ten different subsets. These T cells don’t just remember allergens; they expand and react very quickly when the same allergen comes again, meaning the T cells could be responsible for more severe asthma attacks. Plus, the T cells Sethi uncovered are also programmed to survive for an extended period of time, even in the absence of an allergen, and are highly committed to staying in the lungs for their entire life.
Sethi says the new SPARK funding will help him understand how these T cells work.
“This project will also help us to shed some light on the ‘stem-cell-like’ behavior of these immortal cells, which is one of the ongoing debates in the field of memory T cells,” says Sethi. “These cells may be responsible for the reappearance of the disease after people stop therapy—or the failure of therapy for some patients.”
Indeed, these bad memory T cells, both old and new, appear to drive the return of asthma symptoms in mice who stopped receiving treatment.
Running with a new discovery
“This discovery completely changed our perspective about allergen-induced memory cells,” says Sethi.
His current Tullie and Rickey Families SPARK project revealed that the allergen-reactive memory T cells are not a single population but an extended heterogenous family of different members. Each member of the family is unique. The good thing here is that now we know the genetic profile of each of these populations of cells.
Now, with his additional SPARK award, Sethi is diving into the nature of all of these family members to get the answer to how asthma therapies affect this pool of memory T cells.
“If we are lucky enough, we would know which one is the most notorious member of this bad family, responsible for the long-lasting persistence of this cell population even after getting treatment, and thus responsible for therapy-resistance in asthma patients,” says Sethi. “This research will further help us to understand what different proteins each family member expresses.”
Thanks to the SPARK award, Sethi will also have a chance to compare his findings in allergic mice to T cell activity in human samples. In the end, Sethi hopes his work could discover novel therapeutic targets of bad memory T cells, including the therapy-resistant members that would take us one step closer to ‘long-lasting therapies’ for asthma patients.
After years of watching asthma researchers struggle to help patients, Sethi is feeling hopeful.
“I just want to take this opportunity to say thank you to all the SPARK donors because they decided to come along with me for some extra miles,” Sethi says. “It’s good motivation for any researcher to see their funders still believing in their ideas.”
