Constraints and tunability of antigen-agnostic memory durability

Area of Science:

• Immunology
• Systems Biology
• Computational Biology

Background:

• Infection and vaccination induce antigen-specific immune memory.
• Antigen-agnostic memory, including trained immunity, also forms but its durability is poorly understood.
• Factors limiting the persistence of trained immunity are key research questions.

Purpose of the Study:

• To investigate the determinants of antigen-agnostic immune memory durability.
• To explore mechanisms that can overcome limitations imposed by cell turnover and epigenetic stability.
• To identify how immune cell interactions contribute to long-lasting immunological memory.

Main Methods:

• Development of mathematical models of immune memory dynamics.
• Utilizing computer simulations to explore model behavior.
• Employing machine learning for parameter-phenotype mapping.
• Proposing specific experimental validation strategies.

Main Results:

• Antigen-agnostic memory durability is constrained by immune cell turnover and cytokine dependence.
• Trained immunity persistence is further limited by epigenetic state transmission fidelity.
• Positive feedback via cytokine signaling creates tunable memory with excitable responses and slow relaxation.

Conclusions:

• Cytokine-mediated positive feedback offers a cell-extrinsic mechanism for durable, tunable antigen-agnostic memory.
• This mechanism can overcome inherent constraints of cell turnover and epigenetic inheritance.
• Findings provide a framework for understanding and potentially enhancing long-lasting immune memory.