Self-tolerance: context dependent tuning of T cell antigen recognition.

Physiological messages to cells are encoded in the magnitude, and in the time- and space-contingencies, of sets of stimuli. In particular, individual T cells continuously integrate antigenic and other signals and respond differentially to the rate of change in the level of stimulation, translated intracellularly into 'metabolic perturbations'. The organization of the immune response at the cell-population level in space and time is also conductive to discriminating the magnitude of 'system perturbations'. In this way, the immune system was 'designed' to respond in a characteristic explosive way mainly to episodes of infection and not to the continuous presence of self-antigens. T cells are selected to be moderately autoreactive, and the degree of autoreactivity that they express is continuously controlled through activation-threshold tuning. Their level of autoreactivity is maintained in a range that facilitates survival and self-renewal and is probably used in performing some immunoregulatory functions and possibly other physiological functions. Autoreactivity and outward-directed immunity are regulated simultaneously and interactively through the interplay of selection, tuning, controlled activation and feedback. Copyright 2000 Academic Press.