Novel Microscopy Reveals Two-Stage T-Cell Activation During Viral Infection

Research teams led by Wolfgang Kastenmüller and Georg Gasteiger have used advanced microscopy techniques to study how T-cells—key players in the immune system—activate and multiply during viral infections. Their findings revealed previously unrecognized mechanisms, showing that the immune system enhances its defense response in a more precise and selective way than previously thought.

T-Cells Multiply and Specialize in Response to Infection

T-cells are central to the immune system’s ability to detect and eliminate infected cells. But before they can mount an effective response, the rare T-cells with the right specificity must undergo a process of activation, expansion, and specialization.

This process—known as T-cell priming—begins when T-cells interact with dendritic cells (DCs) in the lymph nodes. These DCs display fragments of pathogens (antigens) and activate the T-cells through complex signaling pathways.

The initial activation phase lasts about 24 hours. During this time, T-cells remain in close contact with DCs, receiving cues that shape their future function. Once primed, they disengage, migrate, and begin to rapidly proliferate.

Some of these T-cells become effector cells, immediately targeting infected cells. Others evolve into memory cells, enabling faster responses to future infections.

The Immune System Selects Only the Most Effective T-Cells

From a vast and diverse pool of T-cells, the immune system must identify those best equipped to recognize a specific pathogen. These selected cells are then expanded during the priming phase.

Katarzyna Jobin and Deeksha Seetharama, the study’s lead authors, uncovered a key detail in this process.

“We discovered that T-cell activation actually involves two distinct phases,” said Seetharama.

While the first phase activates a broad set of potentially useful T-cells, the second—newly identified—phase refines the response. It selects and amplifies only those T-cells that most effectively recognize the pathogen. “This two-step process helps ensure the immune system responds with maximum precision and efficiency,” Seetharama explained.

Wolfgang Kastenmüller added, “Until now, it was assumed that once activated, T-cells operated on autopilot. What we didn’t understand was how the most effective cells were specifically selected.”

New Insights May Inform Future Therapies

The researchers found that T-cell activation isn’t a one-and-done event—it’s cyclical. After their initial activation, T-cells enter a desensitized state for two to three days before they’re ready to receive further signals via their T-cell receptors.

That’s when the second activation phase kicks in. During this phase, T-cells regroup with DCs in specific regions of the lymph nodes, where they receive additional signals that promote further proliferation and specialization. These zones become accessible due to the expression of the CXCR3 receptor on CD8 T-cells.

CD4 helper T-cells also contribute by providing IL-2, a crucial growth signal. Only those CD8 T-cells that strongly bind to antigens—and receive this help—are able to proliferate efficiently. As a result, these high-affinity CD8 T-cells dominate during the peak of the immune response.

This discovery has important implications for immunotherapies, particularly those used in cancer and chronic infections, where T-cell activation and desensitization cycles play a critical role. For instance, CAR T-cell therapies—which involve engineering a patient’s own T-cells to recognize and attack cancer cells—rely on sustained activation for effectiveness.

“These insights deepen our understanding of how to better optimize T-cell-based therapies,” said Georg Gasteiger. “They may also help explain why certain treatments fail, and how we can improve their success.”