Design principles of the cytotoxic CD8⁺ T-cell response

Area of Science:

• Immunology
• Systems Biology
• Computational Biology

Background:

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

Purpose of the Study:

• To model T-cell responses as feedback-controlled programs regulated by immune cues.
• To explore how feedback-controller designs optimize T-cell responses for infection control and minimize immunopathology.
• To investigate T-cell therapy optimization for cancer treatment.

Main Methods:

• Recasting T-cell response as a feedback-controlled program.
• Exploring a class of feedback-controller designs.
• Analyzing signal-feedback optimization for diverse infection settings.
• Modeling T-cell therapies for cancer tumors.

Main Results:

• T-cell response speed and magnitude emerge from optimizing signal-feedback.
• An inherent trade-off exists between infection clearance and immunopathology.
• Immune response designs balancing infection and autoimmunity align with experimental data.
• A trade-off between T-cell affinity and abundance is identified for cancer therapy.
• Targeted genetic perturbations can improve therapeutic efficacy.

Conclusions:

• A unified control logic for CTL responses is proposed.
• Specific regulatory programs can be engineered for enhanced T-cell therapies.
• Findings provide insights into balancing immune response benefits and harms.