STAT3 positively regulates an early step in B-cell development

Abstract

IntroductionB lymphopoiesis involves the expression of multiple factors, including cytokine receptors and transcription factors. [1][2][3] Among the cytokine receptors, Flt3 and IL-7R are known to be critical for early B-cell development. Targeted deletion of Flt3 or Flt3 ligand impairs the development of pro-B and pre-B cells. [4][5][6] Similarly, genetic ablation of the IL-7 or the IL-7R␣ chain results in a developmental block in CLP and pro-B stages. [7][8][9] Mice lacking both Flt3L and IL-7R␣ completely lose B lymphocytes in the BM, suggesting that these 2 molecules do not have completely overlapping functions in B lymphopoiesis. 10 Several transcription factors are also indispensable for B-cell development and function in a sequential and an interdependent manner to instruct the generation of B-cell precursors from hematopoietic progenitors. 11 For instance, PU.1 was first proposed to initiate B-cell differentiation by promoting the expression of IL-7R and EBF, another key transcription factor. 11,12 However, more thorough studies indicated that PU.1 is not strictly required for B lymphopoiesis because mice lacking PU.1 in the B-cell lineage do not display abnormalities in early B-cell development. Nonetheless, abnormalities occur at more mature stages, including a shift of conventional B2 cells to B1 cells in the spleens of the mutant mice. [13][14][15] The upregulation of EBF in conjunction with E2A further facilitates the formation of pro-B cells, where B-cell-specific genes such as Pax5, Ig␣, Ig␤, 5, VpreB, RAG1, and RAG2 are subsequently induced. Although the specification of B cells requires EBF and E2A, commitment and maintenance require Pax5. 2 Although IL-7R signaling activates STAT1, STAT3, and STAT5, it is generally believed that STAT5 plays the major role in IL-7-mediated B lymphopoiesis. [16][17][18][19][20] The expansion of pro-B cells in transgenic mice expressing constitutively active STAT5 correlated with an increase in cyclin D2, pim-1, and bcl-xL expression, suggesting that STAT5 directly affects the proliferation and survival of pro-B cells. 19 Overexpression of this form of STAT5 also restored B-cell differentiation in the IL-7R-deficient mice, including V H immunoglobulin rearrangement and appearance of immature and mature B cells. 19 In addition, a severe deficiency in B lymphopoiesis was observed in the absence of STAT5a/b, resulting in combined immunodeficiency similar to that caused by lack of IL-7 signaling. 17 STAT5 also regulates germline transcription, histone acetylation, and DNA recombination of distal V H gene segments in an IL-7-dependent manner. In the absence of STAT5a/b, these events are greatly impaired. 18 Although STAT1 affects the survival and proliferation of T lymphocytes, contributes to the development of adaptive immune responses, and has a differential effect on the expression of MHC class I in T and B cells, it has not been shown to play a direct role in lymphopoiesis. 21,22 The functions of STAT3 in vivo have been extensively investigated using conditional ge...

Reduction of Stat3 Activity Attenuates HIV-Induced Kidney Injury

“…It has been shown that Stat3 plays a role in T and B cell development. 24,25 We confirmed that knock-down of Stat3 activity and expression of HIV transgene did not affect T and B cell development in these mice. In a prior study, we found that homozygous Tg26 mice had a small thymus, large spleen, and lymphadenopathy.…”

“…BASIC RESEARCH www.jasn.org into the kidney was significantly reduced in Tg26-SA/Ϫ compared with Tg26-SA/ϩ. Because it has been shown that Stat3 plays a role in T and B cell development 24,25 and HIV genes are expressed ubiquitously in Tg26 mice, we sought to determine whether T and B cell development differs between these mice.…”

STAT3 Negatively Regulates Type I IFN-Mediated Antiviral Response

“…Generation and mating of MxCre-STAT3 f/f mice and induction of STAT3 deletion have been described previously (19,20). These animals were maintained and housed in specific germ-free conditions in the Animal Core Facility at the National Taiwan University College of Medicine.…”

Leptin signaling maintains B-cell homeostasis via induction of Bcl-2 and Cyclin D1

“…S1 A and B). Because STAT3 is a major regulator of B-cell development, we examined its activity upon leptin treatment in B cells (18). We found that phosphorylation of STAT3 occurred when leptin was added to spleen B cells in culture, whereas a significantly reduced level of phosphorylated STAT3 was found in db/db mouse B cells (Fig.…”