Suppression of Phosphatidylinositol 3,4,5-Trisphosphate Production Is a Key Determinant of B Cell Anergy
| Autor: | Matthew H. Cato, Hart S. Dengler, Christopher J. Del Nagro, Cecille D. Browne, Robert C. Rickert |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Clonal anergy
Phosphatidylinositol (3 4 5)-trisphosphate B-cell receptor Immunology Biology CD19 Cell biology chemistry.chemical_compound Tolerance induction medicine.anatomical_structure Infectious Diseases chemistry Biochemistry CELLIMMUNO biology.protein medicine PTEN Immunology and Allergy MOLIMMUNO PI3K/AKT/mTOR pathway B cell |
| Zdroj: | Immunity. 31(5):749-760 |
| ISSN: | 1074-7613 |
| DOI: | 10.1016/j.immuni.2009.08.026 |
| Popis: | SummaryAnergy is a critical physiologic mechanism to censor self-reactive B cells. However, a biochemical understanding of how anergy is achieved and maintained is lacking. Herein, we investigated the role of the phosphoinositide 3-kinase (PI3K) lipid product PI(3,4,5)P3 in B cell anergy. We found reduced generation of PI(3,4,5)P3 in anergic B cells, which was attributable to reduced phosphorylation of the PI3K membrane adaptor CD19, as well as increased expression of the inositol phosphatase PTEN. Sustained production of PI(3,4,5)P3 in B cells, achieved through conditional deletion of Pten, resulted in failed tolerance induction and abundant autoantibody production. In contrast to wild-type immature B cells, B cell receptor engagement of PTEN-deficient immature B cells resulted in activation and proliferation, indicating a central defect in early B cell responsiveness. These findings establish repression of the PI3K signaling pathway as a necessary condition to avert the generation, activation, and persistence of self-reactive B cells. |
| Databáze: | OpenAIRE |
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