  A cornerstone of the classical view of tolerance is the elimination of
self-reactive T cells during negative selection in the thymus. However,
high-throughput T-cell receptor sequencing data has 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 can 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 explain the plasticity of the immune system and its robustness to
autoimmunity.
