Understanding how ‘first responder’ cells alert and control immune response

When an outside pathogen enters our bodies, our immune system responds with its army of white blood cells and antibodies. But who sends out the marching orders to this network?

A certain kind of immune cell called a dendritic cell sends out the initial call, scientists and engineers have learned. But many in the field have debated just how these cells do this. Do they all send out signals simultaneously? Or does a smaller group reach a consensus and then tell the others what to do, like social media influencers?

To find out, Assoc. Prof. Aaron Esser-Kahn and his team in the Pritzker School of Molecular Engineering (PME) at the University of Chicago isolated these dendritic cells in a mouse model and found that a small subset act as “first responders,” gathering information and signaling to other cells to respond.

Aaron Esser-Kahn
Assoc. Prof. Aaron Esser-Kahn

They also found out just how important these cells are to immune response. When the signaling ability of these first responders is removed, the whole communication network collapses, and the immune system does not respond at all. “These first responder cells aren’t just influencers—they have a level of control that hasn’t been appreciated before,” Esser-Kahn said.

The results, which could have implications for vaccine design and autoimmune disease therapy, were published in Cell Reports.

First responders emerge from dendritic cell population

Esser-Kahn and his group began to study this phenomenon after they noticed an interesting result while researching vaccine adjuvants, ingredients added to vaccines to elicit a stronger immune response. They found that a large amount of these adjuvants ended up in a small percentage of dendritic cells.

Esser-Kahn’s team studied the cells and found signature proteins on their surface, allowing the team to easily identify and isolate the cells for more direct study.

What the team found surprised them. These dendritic cells weren’t like the others. A small subset—about 5 percent—had taken on new characteristics that allowed them to identify the invader—in this case, a vaccine administered by the team—and begin alerting other cells. These abilities only lasted for a short time, about 30 minutes.

“It turned out that at any given time, 5 percent of these dendritic cells take on this unique state, stay that way for a short time, then go back into the regular population,” Esser-Kahn said. “That’s why scientists had missed it before—because the percentage is so small and it happens for such a short period of time.”

Incapacitating cells to diminish immune response

Isolating these cells also allowed the team to understand what happens when these first responders aren’t there. By adding a chemical that cripples the ability of these first responder cells to communicate, then introducing a vaccine, they could better understand the role the cells played. In a mouse model, the team found that disrupting this communication eliminated the immune response to the vaccine completely, rendering the vaccine inert.

“We were surprised that we were able to diminish the immune response as much as we did,” Esser-Kahn said.

The finding poses interesting questions about preventing and treating disease. To elicit the best response, should vaccines just communicate with these first responder cells? Or could these first responder cells be tamped down as a new way to treat autoimmune diseases?

““The understanding that we gained allows us to see how the process works, and the next step is thinking about what we can do with that information,” Esser-Kahn said.

Other authors on the paper include postdoctoral researcher Peter Deak, graduate students Bradley Studnitzer and Trevor Ung, Prof. Melody Swartz, and Rachel Steinhardt of Syracuse University.

Citation: “Isolating and Targeting a Highly Active, Stochastic Dendritic Cell Subpopulation for Improved Immune Responses,” Deak et al, Cell Reports, November 1, 2022. DOI: