Overexpression of Bcl‐3 inhibits the development of marginal zone B cells

Abstract

The transcription factor Bcl-3 functions as a proto-oncogene via regulation of cell proliferation and apoptosis. Bcl-3 is an atypical member of the IκB family and plays a central role in the immune response through interactions with the NF-κB subunits p50 and p52. To investigate the impact of Bcl-3 on B-cell maturation and regulation, we generated mice that overexpress Bcl-3 specifically in B cells. Interestingly, these mice lack marginal zone B cells and exhibit a significant reduction in the number of B-1 B cells. Further, B cells from these mice are impaired in their proliferative capacity. Our data demonstrate that the overexpression of the transcription factor Bcl-3 inhibits germinal center formation, marginal zone B-cell development, and affects the B-1 B-cell compartment.Keywords: B-1 B cells r Bcl-3 r Marginal zone B cell r NF-κB Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe Bcl-3 gene was first identified in a translocation into the Ig alpha locus in various cases of B-cell chronic lymphocytic leukemia [1,2]. The oncogene Bcl-3 encodes for an atypical member of the inhibitor of kappa B (IκB) family of proteins. Although Bcl-3 has high structural homology to the other IκB family members, Bcl-3 fails to inhibit NF-κB molecules in the cytoplasm but instead is a nuclear protein with both activating and repressing functions [3,4]. Specific domains within Bcl-3 can stimulate transcription through interaction with p50 and p52 homodimers [3,5]. So far Bcl-3 has also been implicated in various gene regulatory networks and biological processes [6,7] but its physiological mechanisms of action and in vivo targets remain largely unknown.Correspondence: Dr. Nadine Hövelmeyer e-mail: hoevelme@uni-mainz. de In order to study the role of Bcl-3 in lymphoid malignancies, Tg animals were generated overexpressing Bcl-3 in B and T cells. These mice exhibit splenomegaly and an accumulation of mature B cells in secondary lymphoid organs, but fail to develop lymphoid neoplasms. These mice show an increased response to crosslinking of surface IgM [8]. On the other hand, Bcl-3-deficient mice demonstrate the requirement for Bcl-3 in germinal center (GC) formation and in the production of Ag-specific antibodies [9,10]. Naïve B cells are generally divided into three subsets, B-1 B cells, follicular (FO), and marginal zone (MZ) B cells, whereas MZ B cells play a central role in eliciting Ab response against bloodborn pathogens. These B cells reside within the MZ located outside the marginal sinus and are the juncture of white and red pulp in the spleen. The factors that regulate the homeostasis of MZ B cells are not completely understood. Immature B cells that emigrate * These authors contributed equally to this work. from the bone marrow into the spleen develop through distinct transitional B-cell stages, termed as T1, T2, and T3 [11]. The T2 transitional B cell is thought to be the common precursor for both MZ and FO B cells [12]. FO B cells can b...

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mTORC1 activation in B cells confers impairment of marginal zone microarchitecture by exaggerating cathepsin activity

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