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- Title
A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens.
- Authors
Sindhava, Vishal J.; Oropallo, Michael A.; Moody, Krishna; Naradikian, Martin; Higdon, Lauren E.; Lin Zhou; Myles, Arpita; Green, Nathaniel; Nündel, Kerstin; Stohl, William; Schmidt, Amanda M.; Wei Cao; Dorta-Estremera, Stephanie; Kambayashi, Taku; Marshak-Rothstein, Ann; Cancro, Michael P.; Zhou, Lin; Cao, Wei
- Abstract
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.
- Subjects
B cell differentiation; APOPTOTIC bodies; CELL anatomy; PROLIFERATIVE vitreoretinopathy; HUMORAL immunity; ANIMAL experimentation; ANIMALS; ANTIGENS; B cells; CELL differentiation; CELL lines; CELL receptors; CELLULAR signal transduction; DNA; INTERFERONS; INTERLEUKINS; MICE; PROTEINS; RESEARCH funding; TRANSFERASES; TUMOR necrosis factors
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 5, p1651
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI89931