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

VJ Sindhava, MA Oropallo, K Moody… - The Journal of …, 2017 - Am Soc Clin Investig
VJ Sindhava, MA Oropallo, K Moody, M Naradikian, LE Higdon, L Zhou, A Myles, N Green…
The Journal of clinical investigation, 2017Am Soc Clin Investig
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 …
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.
The Journal of Clinical Investigation