Transcription Factor ABF-1 Suppresses Plasma Cell Differentiation but Facilitates Memory B Cell Formation

Abstract

Ag-primed B cells that result from an immune response can form either memory B cells or Ab-secreting plasma cells; however, the molecular machinery that controls this cellular fate is poorly understood. In this study, we show that activated B cell factor-1 (ABF-1), which encodes a basic helix-loop-helix transcriptional repressor, participates in this regulation. ABF-1 was prevalently expressed in purified memory B cells and induced by T follicular helper cell–mediated signals. ABF-1 expression declined by the direct repression of B lymphocyte–induced maturation protein-1 during differentiation. Ectopic expression of ABF-1 reduced the formation of Ab-secreting cells in an in vitro differentiation system of human memory B cells. Accordingly, knockdown of ABF-1 potentiates the formation of Ab-secreting cells. A transgenic mouse that expresses inducible ABF-1 in a B cell–specific manner was generated to demonstrate that the formation of germinal center and memory B cells was augmented by induced ABF-1 in an immune response, whereas the Ag-specific plasma cell response was dampened. This effect was associated with the ability of ABF-1 to limit cell proliferation. Together, our results demonstrate that ABF-1 facilitates formation of memory B cells but prevents plasma cell differentiation.

O-GlcNAcylation is required for B cell homeostasis and antibody responses

“…Four weeks after primary immunization, mice were injected with 100 μg NP 32 -KLH for the secondary immunization. In one experiment, bone marrow cells (1 × 10 6 cells) isolated from Ctrl and Cγ1-KO mice at 4 weeks after the secondary immunization with NP-KLH were subjected to ELISPOT analysis to test the number of NP-specific IgG-secreting plasma cells as follows 44 : B cells were seeded into a 96-well plate and incubated on nitrocellulose membranes (Bio-Rad), which was coated with NP 32 -BSA (100 μg ml −1 , Biosearch technologies), at 37 °C for 2.5 h. Attached cells were lysed by PBS-EDTA for 15 min, followed by two washes with 0.1% Tween 20 in PBS and one wash in PBS. The membrane was incubated at room temperature for 30 min with PBS and 1% bovine serum albumin (BSA), followed by incubation with anti-mouse IgG (Southern Biotechnology) at a dilution of 1000 × in PBS plus 1% BSA at room temperature for 1 h. NP-specific IgG-secreting cells were then visualized by the addition of enzyme substrate.…”

Helix–loop–helix proteins and the advent of cellular diversity: 30 years of discovery

“…In maturing B cells, E2A as well as E2-2 continue their activities to promote plasma cell differentiation, whereas the HLH protein ABF1 instructs germinal center cells to adopt the memory B-cell fate (Fig. 5;Massari et al 1998;Chiu et al 2014;Gloury et al 2016;Wöhner et al 2016). Finally, two additional HLH proteins-Bhlhe40 (Dec2) and Bhlhe41 (Dec1)-orchestrate the selfrenewal activity and development of B1 cells (Fig.…”

The Transcriptional Regulation of Germinal Center Formation

“…Prdm1 is a downstream target of IRF4, and BLIMP1 can further increase the level of IRF4, thus reinforcing the plasma cell differentiation program in a feed forward loop ( 26 , 79 ). Morever, BLIMP1 represses the expression of Aicda ( 79 ) and Abf-1 ( 80 ).…”

“…Activated B cell Factor 1 (ABF-1), a helix-loop-helix TF predominantly expressed in memory B cells, blocks the plasma cell differentiation program ( 80 ). An inducible ABF-1-ER mouse model demonstrated that induction of ABF-1 promotes GC formation and memory B cell differentiation ( 80 , 97 ). ZBTB32 and KLF2 are two factors expressed in memory B cells and which inhibit the GC response ( 98 ).…”