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 and malignant cells.
• The underlying design principles governing CTL response speed and magnitude remain unclear.
• Existing research has cataloged many molecular and cellular components of immune responses.

Purpose of the Study:

• To model CTL responses as a feedback-controlled program regulated by various immune cues.
• To understand how signal-feedback optimization influences CTL response speed and magnitude.
• To explore the trade-offs between infection clearance and immunopathology.

Main Methods:

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

Main Results:

• Identified an inherent trade-off between infection clearance and immunopathology.
• Demonstrated that hierarchical sensitivity to immune signals encodes this trade-off.
• Observed that optimized designs align with experimental T cell expansion patterns in mice.
• Quantified the quality-quantity trade-off for T cell therapies against tumors.

Conclusions:

• Proposed a unified control-logic for CTL responses.
• Highlighted specific regulatory programs for engineering robust T cell therapies.
• Showed that targeted genetic perturbations can improve therapeutic efficacy.