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

作者：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.^*

来源：Journal of Clinical Investigation, 2017, 127(5): 1651-1663.

DOI：10.1172/JCI89931

• SYSTEMIC-LUPUS-ERYTHEMATOSUS
• TOLL-LIKE RECEPTOR-9
• AUTOANTIBODY PRODUCTION
• MARGINAL ZONE
• CUTTING EDGE
• T-CELLS
• LYMPHOCYTE STIMULATOR
• SOMATIC MUTATION
• ESCAPE TOLERANCE
• INTERFERON-GAMMA

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 G(1) 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-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(+) 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.

• 出版日期2017-5-1
• 单位中国人民解放军第二军医大学; 天津市中医药研究院附属医院