Motheaten viable (me*) mice are deficient in the cytosolic protein tyrosine phosphatase, PTPlC, and exhibit severe B cell immunodeficiency and autoantibody production. The role of PTPl C in B cell selection and function was analyzed by breeding immunogiobulin transgenes specific for a defined antigen, hen egg iysozyme, into me’mice. Antigen triggered a greater and more rapid elevation of intracellular calcium in PTPlC-deficient B cells, indicating that this phosphatase negatively regulates immunogiobuiin signaling. Elimination of self-reactive B cells carrying this signaienhancing mutation was triggered during their development by binding a lower valency form of self-antigen than is normally required. These findings establish that activation of distinct repertoire-censoring mechanisms depends on quantitative differences in antigen receptor signaling, whose thresholds are determined by negative regulation through PTPlC. introduction

Signaling by cell surface antigen receptors coordinates development and selection of B and T lymphocytes. Prior to infection, antigen receptor signaling in response to selfantigens underlies negative and positive selection steps that determine which clones mature to form the preimmune repertoire of circulating lymphocytes and ensure self-tolerance. Following infection, binding of foreign antigens triggers clonal expansion of specific cells and production of antigen-specific antibody. Each of these selection steps depends on the existence of signaling thresholds. For example, negative selection must be limited to clones that bind self-antigens avidly to avoid eliminating too large a fraction of the preimmune repertoire, and clonal expansion in response to foreign antigens must be skewed to favor cells expressing antibodies with the highest possible affinity. Despite the broad significance of these limits for normal immunological function, little is known of the intracellular signaling molecules that help define such thresholds.