Continuous inhibitory signaling by both SHP-1 and SHIP-1 pathways is required to maintain unresponsiveness of anergic B cells.
Many autoreactive B cells persist in the periphery in a state of unresponsiveness called anergy. This unresponsiveness is rapidly reversible, requiring continuous BCR interaction with self-antigen and resultant regulatory signaling for its maintenance. Using adoptive transfer of anergic B cells with subsequent acute induction of gene deletion or expression, we demonstrate that the continuous activities of independent inhibitory signaling pathways involving the tyrosine phosphatase SHP-1 and the inositol phosphatase SHIP-1 are required to maintain anergy. Acute breach of anergy by compromise of either of these pathways leads to rapid cell activation, proliferation, and generation of short-lived plasma cells that reside in extrafollicular foci. Results are consistent with predicted/observed reduction in the Lyn-SHIP-1-PTEN-SHP-1 axis function in B cells from systemic lupus erythematosus patients.
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Andrew
A
Getahun
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Nicole A
NA
Beavers
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206.
Sandy R
SR
Larson
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.
Mark J
MJ
Shlomchik
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 Department of Biomedical Research, National Jewish Health, Denver, CO 80206 John.Cambier@ucdenver.edu.
John C
JC
Cambier
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D017635:Clonal Anergy; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000276:immunology; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / Q000235:genetics / Q000276:immunology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D019061:src-Family Kinases / Q000235:genetics / Q000276:immunology
C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases