Beyond self and nonself: Fuzzy recognition of the immune system

Self-nonself discrimination of the immune system is a widely accepted principle of immunology; however, abundant existing and physiologic functions of harmless autoimmunity as well as degeneracy of antigen recognition expose the over-simplification of the two-valued doctrine. Here, based on infinite-value fuzzy logic, we propose that the immune repertoire, as a consequence of central tolerance, is able to recognize both self and nonself antigens to a certain degree, compensating for the inadequacy of the two-valued self-nonself doctrine. Subthreshold recognition of self antigens is necessary for the generation of regulatory T cells, survival of both naive and memory T cells and other physiologic functions. The kind and magnitude of the immune response depend on the affinity between the antigen (self and foreign) and the T-cell receptor, and microenvironmental and cellular threshold. The outcome of self-nonself discrimination is influenced fundamentally by central tolerance and further dynamic regulation of threshold molecules both in time and space. Understanding the fuzzy feature of the immune system may shed light on mechanisms of autoimmune diseases, cancers and other chronic diseases, and lead to the design of novel vaccines or immunotherapies.