Design principles of the cytotoxic CD8⁺ T-cell response

Area of Science:

• Immunology
• Systems Immunology
• Computational Biology

Background:

• Cytotoxic T lymphocytes (CTLs) are crucial for eliminating infected and malignant cells.
• Understanding the design principles governing CTL response speed and magnitude from cellular decisions is challenging.

Purpose of the Study:

• To model T-cell responses as feedback-controlled programs.
• To investigate how signal-feedback design influences response speed, magnitude, and the trade-off between infection clearance and immunopathology.
• To explore implications for T-cell therapies.

Main Methods:

• Recasting T-cell response dynamics as a feedback-controlled program.
• Analyzing a broad class of feedback-controller designs.
• Modeling immune response to diverse infection settings.
• Extending the model to cancer T-cell therapies.

Main Results:

• T-cell response speed and magnitude emerge from optimizing signal-feedback.
• An inherent trade-off exists between infection clearance and immunopathology, encoded by hierarchical signal sensitivity.
• Model predictions align with experimental T-cell expansion patterns in mice.
• Identified quality-quantity trade-offs in T-cell cancer therapies.
• Demonstrated potential for improving therapeutic efficacy via genetic perturbations.

Conclusions:

• A unified control logic for CTL responses can be established.
• Specific regulatory programs can be engineered for enhanced T-cell therapies.
• Findings provide insights into balancing immune protection and self-harm.