STAT3 Positively Regulates an Early Step in B Cell Development
Date Issued
2008
Date
2008
Author(s)
chou, wei-chun
Abstract
B lymphopoiesis involves the expression of multiple factors, including cytokine receptors and transcription factors. Among the cytokine receptors, Flt3 and IL-7R are known to be critical for early B-cell development. Likewise, transcription factors including E2A, EBF, and Pax5 are critical for specification and commitment of the development of B lymphocytes from multipotential progenitor cells in the bone marrow (BM). Here, we show that the absence of STAT3 impaired B-cell development. Mice selectively lacking STAT3 in BM progenitor cells displayed reduced numbers of mature B cells, both in the BM and in the periphery. The reduction in the B-cell compartment included reduced percentages and numbers of pro-B, pre-B, and immature B cells in the absence of STAT3, whereas the number of pre-pro-B cells was increased. We found that pro-B and pre-B-cell populations lacking STAT3 were hyporesponsive to IL-7 because of a decreased number of IL-7-responsive cells rather than decreased expression of IL-7Rα or reduced activation of STAT1 and STAT5 downstream of IL-7/IL-7Rα signaling. Moreover, STAT3-deficient mice displayed enhanced apoptosis in the pro-B population when deprived of survival factors, suggesting that at least two mechanisms (impaired proliferation and enhanced apoptosis) are involved in the mutant phenotype. Likewise, the expression of anti-apoptotic molecule Mcl-1 in response to IL-7 was slightly reduced in STAT3KO mice. Last, BM transplantation confirmed that impaired B lymphopoiesis in the absence of STAT3 was caused by a cell autonomous defect. oreover, we found that the expression of B cell specific regulators such as EBF, E2A, Pax5, Rag1/2, TdT, VpreB, λ5, Igα, and Igβ was comparable in control and STAT3KO cells. Interestingly, the dramatic reduced of distal VHJ558 germline and rearranged transcriptions were shown in the absence of STAT3. In addition, we also found that the reduced IL-7-responsive progenitors might due to the insufficient proliferative ability of progenitors in response to Flt3L by the in vitro culture of Lin-c-kit+IL-7Rα+ progenitors that were differentiated into B220+ IL-7Rα+ cells. n sum, these studies defined a specific role for STAT3 in early B-cell development, probably acting at or before the pre-pro-B transition by contributing to the survival and proliferation of Flt3L or IL-7-responsive progenitors.
Subjects
STAT3
B cell development
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