A TLR9-dependent checkpoint governs B cell responses to DNA-containing antigens

Mature B cell pools retain a substantial proportion of polyreactive and self-reactive donotypes, suggestingthat 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 t...

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Bibliographic Details
Published in:The Journal of clinical investigation 2017-05, Vol.127 (5), p.1651
Main Authors: Sindhava, Vishal J, Oropallo, Michael A, Moody, Krishna, Naradikian, Martin, Higdon, Lauren E, Zhou, Lin, Myles, Arpita, Green, Nathaniel, Nundel, Kerstin, Stohl, William, Schmidt, Amanda M, Cao, Wei, Dorta-Estremera, Stephanie, Kambayashi, Taku, Marshak-Rothstein, Ann, Cancro, Michael P
Format: Article
Language:English
Subjects:
Antigens
B cells
Cellular signal transduction
Cytokine receptors
DNA
TLR9
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Summary:Mature B cell pools retain a substantial proportion of polyreactive and self-reactive donotypes, suggestingthat 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 [G.sub.1] cell-cycle arrest and subsequent intrinsic mitochondrial apoptosis and is shared by all preimmune murine B cell subsets and [CD27.sup.-] 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-[gamma] 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.sup.+] 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.sup.+] phenotype.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI89931.