A Balance between B Cell Receptor and Inhibitory Receptor Signaling Controls Plasma Cell Differentiation by Maintaining Optimal Ets1 Levels

Abstract

Signaling through the B cell receptor (BCR) can drive B cell activation and contribute to B cell differentiation into antibody-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. Here, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is down regulated in B cells by BCR or TLR signaling through a pathway dependent on PI3 kinase, Btk, IKK2 and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase SHP1 or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.

Cellular Differentiation Regulator BLIMP1 Induces Epstein-Barr Virus Lytic Reactivation in Epithelial and B Cells by Activating Transcription from both the R and Z Promoters

“…Given that EBV is reactivated in one type I latency BL cell line, Akata, with BLIMP1 alone while two others, MutuI and KemI, require TPA along with BLIMP1, we hypothesize that there exists a balance of cellular transcription factors and pathways necessary for BLIMP1-induced reactivation that is already present (or absent) in Akata cells, with TPA modifying their levels and/or activities in MutuI and KemI cells and altering them somewhat in Sal, Oku, and KemIII cells. For example, one such factor may be the cellular transcription factor Ets-1; it can bind BLIMP1, inhibiting its activity (89,90), while expression of Ets-1 is inhibited in B cells by incubation with TPA (91,92). BLIMP1 versus BLIMP1␤.…”

The Role of the Transcription Factor Ets1 in Lupus and Other Autoimmune Diseases

“…19 However, mixed bone marrow chimeras generated with allotype-labeled wildtype and Ets1 deficient fetal liver cells showed that the Ets1-deficient B cells give rise to increased numbers of plasma cells as compared with wild-type B cells developing in the same host. 85 Therefore, there are likely both B cell-intrinsic and B cell-extrinsic functions of Ets1 that together promote B cell activation and autoantibody secretion. These will be described in detail below.…”

“…85 In mice lacking Ets1, B cells are hyper-activated as shown by increased expression of activation markers, 19 increased isotype-switching to IgG1 and IgE 18,79 and increased propensity to terminally differentiate into plasma cells secreting IgM and IgG. 19,74,77,78 These observations suggest that Ets1 may play a role in retaining B cells in a resting state.…”

“…19 Purified Ets1 −/− B cells also undergo increased differentiation to plasma cells when cultured with TLR ligands such as oligonucleotides containing unmethylated CpG sequences (TLR9 ligand) 19 or bacterial lipopolysaccharide (TLR4 ligand). 85 This suggests that Ets1 may be particularly important in regulating TLR responses. Nguyen et al .…”

“…79 The enhanced in vitro differentiation and Ig secretion of Ets1 −/− B cells can be suppressed by enforced expression of Ets1 via a retroviral construct. 74,77,85,86 Taken together, it is clear that Ets1 expression is a critical block to plasma cell differentiation and it has B cell-intrinsic roles in regulating this process.…”