A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens
| Autor: | Taku Kambayashi, Amanda M. Schmidt, Krishna Moody, Ann Marshak-Rothstein, Nathaniel M. Green, Michael A. Oropallo, William Stohl, Vishal J. Sindhava, Stephanie Dorta-Estremera, Lauren E. Higdon, Martin S. Naradikian, Kerstin Nündel, Arpita Myles, Lin Zhou, Michael P. Cancro, Wei Cao |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Cell cycle checkpoint MAP Kinase Signaling System medicine.medical_treatment Cellular differentiation B-cell receptor Receptors Antigen B-Cell p38 Mitogen-Activated Protein Kinases Cell Line Interferon-gamma Mice 03 medical and health sciences Antigen B-Cell Activating Factor medicine Animals Antigens CD40 Antigens B-cell activating factor B cell Mice Knockout B-Lymphocytes CD40 biology Chemistry Interleukins Cell Differentiation DNA General Medicine G1 Phase Cell Cycle Checkpoints Cell biology 030104 developmental biology medicine.anatomical_structure Cytokine Toll-Like Receptor 9 biology.protein Female T-Box Domain Proteins Research Article |
| Zdroj: | Journal of Clinical Investigation. 127:1651-1663 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci89931 |
| Popis: | Mature B cell pools retain a substantial proportion of polyreactive and self-reactive clonotypes, suggesting that activation checkpoints exist to reduce the initiation of autoreactive B cell responses. Here, we have described a relationship among the B cell receptor (BCR), TLR9, and cytokine signals that regulate B cell responses to DNA-containing antigens. In both mouse and human B cells, BCR ligands that deliver a TLR9 agonist induce an initial proliferative burst that is followed by apoptotic death. The latter mechanism involves p38-dependent G1 cell-cycle arrest and subsequent intrinsic mitochondrial apoptosis and is shared by all preimmune murine B cell subsets and CD27– human B cells. Survival or costimulatory signals rescue B cells from this fate, but the outcome varies depending on the signals involved. B lymphocyte stimulator (BLyS) engenders survival and antibody secretion, whereas CD40 costimulation with IL-21 or IFN-γ promotes a T-bet+ B cell phenotype. Finally, in vivo immunization studies revealed that when protein antigens are conjugated with DNA, the humoral immune response is blunted and acquires features associated with T-bet+ B cell differentiation. We propose that this mechanism integrating BCR, TLR9, and cytokine signals provides a peripheral checkpoint for DNA-containing antigens that, if circumvented by survival and differentiative cues, yields B cells with the autoimmune-associated T-bet+ phenotype. |
| Databáze: | OpenAIRE |
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