Protein tyrosine phosphatase 1C negatively regulates antigen receptor signaling in B lymphocytes and determines thresholds for negative selection.
Motheaten viable (mev) mice are deficient in the cytosolic protein tyrosine phosphatase, PTP1C, and exhibit severe B cell immunodeficiency and autoantibody production. The role of PTP1C in B cell selection and function was analyzed by breeding immunoglobulin transgenes specific for a defined antigen, hen egg lysozyme, into mev 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.
Cyster
J G
JG
Department of Microbiology and Immunology, Beckman Center, Stanford University School of Medicine, California 94305, USA.
Goodnow
C C
CC
D000818:Animals; D000916:Antibody Diversity / Q000502:physiology*; D000941:Antigens / Q000276:immunology; D016175:B-Lymphocyte Subsets; D001853:Bone Marrow / Q000473:pathology; D002118:Calcium / Q000502:physiology; D007072:Immunoglobulin D / Q000276:immunology*; D007075:Immunoglobulin M / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D017634:Self Tolerance; D015398:Signal Transduction / Q000502:physiology
D000941:Antigens; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D009113:Muramidase; D002118:Calcium