New phase of the immune response discovered

Only the T cells best adapted to the "enemy" undergo the second activation phase

First trained, then selectively activated: The "killer cells" of our immune system are prepared for action in two phases instead of just one, as researchers have discovered. In the first phase, the T cells learn the characteristics of the pathogens they are to destroy. In the second, newly discovered phase, however, only the T cells that best recognize the pathogens are activated and dispatched, as the team reports in "Science." This explains how the immune system ensures the most efficient defense against pathogens.

As "killer cells" of our immune system, T cells play an important role in specifically fighting pathogens. © cgtoolbox/ Getty Images

When pathogens invade our body, the adaptive immune response reacts with a double blow: The production of specific antibodies against the pathogens begins, and at the same time, T cells—the "killer cells" of the immune system—are prepared for action in the lymph nodes. During this T cell activation, known as priming, helper cells present characteristic fragments of the virus's or bacteria's surface proteins to the T cells. CD8 T cells use these antigens to recognize their future opponent.

This "training" of the T cells typically lasts 24 hours. During this time, the defense cells multiply and gradually specialize in the target pathogen. Only then does their rapid proliferation begin and they are released into the body. However, it was previously unclear how the immune system manages to select from the many different T cells those that are most effective against the pathogens for activation and proliferation.

First comes the training

Katarzyna Jobin from the University of Würzburg and her colleagues have now found the surprising answer: T cell priming involves not just one phase, as previously thought, but two. For their study, the team examined the processes in the lymph nodes of mice using fluorescent markers and microscopy.

For T cells to become efficient, pathogen-specific "killer cells," they must first learn the identifying features of their "enemy" and develop appropriate docking sites on their surface.© tttsz/ Getty images

This revealed that, as already known, the T cells are first "trained" by binding to the antigen-presenting dendritic cells. "Afterward, the CD8 T cells detach and can migrate freely in the lymph node," explain Jobin and her colleagues. Under the influence of cytokine messengers, the slightly differently pre-formed T cells now begin to multiply. Until now, it was thought that all subsequent steps in their activation occurred largely automatically.

Then, selection and activation

But this is not the case. Instead, the T cells undergo a second phase two to three days after infection. "During this phase, a subset of CD8 T cells reattaches to the antigen-presenting dendritic cells – this can take several hours," the researchers report. Only these T cells receive special messenger signals in the form of interleukin-2, which then initiate their rapid multiplication and activation.

The crucial point here: As the analyses revealed, only those "killer cells" that are particularly well adapted to the pathogen undergo this second phase. "The second priming phase thus shapes the affinity spectrum of the developing T cell response," explain Jobin and her team. Only those T cells that can identify the pathogen well enough after the first training phase are selected for this second phase.

Two phases of CD8 T cell priming.

A model outlining the activation and subsequent selection of CD8 T cells during priming. In the activation phase (day 1), naïve T cells are recruited from a diverse repertoire and engage with DC for about 24 hours. After activation, T cells desensitize, detach from the DC, proliferate, and move to deeper areas of the lymph node. In the selection phase, activated T cells regain sensitivity (day 2 to 3) allowing high-affinity clones to reengage with antigen-presenting cells. At this stage, they receive critical aid from CD4 T cells that provide IL-2 through a stop-and-go migration pattern. Regulatory T (Treg) cells limit IL-2 availability as they migrate within the T cell zone. These processes collectively drive the expansion and effector differentiation of high-affinity CD8 T cells. Teff, effector T cell. [Figure created with BioRender.com] souce:https://www.science.org/doi/10.1126/science.adq1405

"While the first phase of priming serves to activate as many specific T cells as possible, the newly discovered second phase serves to select and specifically proliferate those that can best recognize the pathogen," says Jobin. "This ensures that the immune response is as efficient as possible."

Also important for cancer immunotherapy

The new findings are not only important for better understanding the immune response to infections and vaccinations. They could also be important for cancer immunotherapy. The body's own T cells play a crucial role here, too: They are removed, genetically modified in the laboratory, and then reintroduced into the body as an infusion. These so-called CAR T cells can then better recognize and fight cancer cells.

"We hope that our new findings will contribute to a deeper understanding of how to optimize T-cell-based therapeutic approaches. And that we will better understand why these therapies sometimes fail," explains senior author Georg Gasteiger from the University of Würzburg.

(Science, 2025; doi: 10.1126/science.adq1405)

Source: Julius-Maximilians-Universität Würzburg, Science