Towards a quantitative theory of tolerance

Area of Science:

• Immunology
• Computational Biology
• Theoretical Biology

Background:

• Classical immunology posits that self-reactive T cells are eliminated via thymic negative selection.
• High-throughput T cell receptor (TCR) sequencing data and experimental evidence challenge this view, suggesting incomplete elimination of self-reactive T cells.

Purpose of the Study:

• To reconcile theoretical models of immune tolerance with empirical observations of incomplete negative selection.
• To propose a unified quantitative theory explaining immune system plasticity and autoimmunity resistance.

Main Methods:

• Discussion of recent theoretical frameworks for immune tolerance.
• Integration of concepts like quorum sensing and dynamic tuning.
• Analysis of T cell receptor (TCR) sequencing data and quantitative estimates.

Main Results:

• Observed T cell repertoires lack substantial signatures of negative selection.
• Quantitative estimates and experiments indicate incomplete elimination of self-reactive T cells.
• Theoretical models incorporating collective decision-making and dynamic adaptation offer potential explanations.

Conclusions:

• A unified quantitative theory of tolerance is needed, integrating collective decision-making and dynamic adaptation.
• These elements may explain the immune system's plasticity and robustness against autoimmunity.
• Revisiting the classical view of tolerance is necessary in light of new data and theoretical insights.