PROTEIN-TYROSINE-PHOSPHATASE 1C NEGATIVELY REGULATES ANTIGEN RECEPTOR SIGNALING IN B-LYMPHOCYTES AND DETERMINES THRESHOLDS FOR NEGATIVE SELECTION

Motheaten viable (me(v)) mice are deficient in the cytosolic protein tyrosine phosphatase, PTP1C, and exhibit severe B cell immunodeficiency and autoantibody production. The role of PTP1C in a cell selection and function was analyzed by breeding immunoglobulin transgenes specific for a defined antigen, hen egg lysozyme, into me(v) mice. Antigen triggered a greater and more rapid elevation of intracellular calcium in PTP1C-deficient B cells, indicating that this phosphatase negatively regulates immunoglobulin signaling. Elimination of self-reactive B cells carrying this signal-enhancing 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 PTP1C.