Towards a quantitative theory of tolerance

A cornerstone of the classical view of tolerance is the elimination of self-reactive T cells via negative selection in the thymus. However, high-throughput T cell receptor (TCR) sequencing data have so far failed to detect substantial signatures of negative selection in the observed repertoires. In addition, quantitative estimates as well as recent experiments suggest that the elimination of self-reactive T cells is at best incomplete. We discuss several recent theoretical ideas that might explain tolerance while being consistent with these observations, including collective decision-making through quorum sensing, and sensitivity to change through dynamic tuning and adaptation. We propose that a unified quantitative theory of tolerance should combine these elements to help to explain the plasticity of the immune system and its robustness to autoimmunity.