Restricted STAT5 Activation Dictates Appropriate Thymic B versus T Cell Lineage Commitment

Abstract

The molecular mechanisms regulating lymphocyte lineage commitment remain poorly characterized. To explore the role of the IL7R in this process, we generated transgenic mice that express a constitutively active form of STAT5 (STAT5b-CA), a key downstream IL7R effector, throughout lymphocyte development. STAT5b-CA mice exhibit a 40-fold increase in pro-B cells in the thymus. As documented by BrdU labeling studies, this increase is not due to enhanced B cell proliferation. Thymic pro-B cells in STAT5b-CA mice show a modest increase in cell survival (∼4-fold), which correlates with bcl-xL expression. However, bcl-xL transgenic mice do not show increases in thymic B cell numbers. Thus, STAT5-dependent bcl-xL up-regulation and enhanced B cell survival are not sufficient to drive the thymic B cell development observed in STAT5b-CA mice. Importantly, thymic pro-B cells in STAT5b-CA mice are derived from early T cell progenitors (ETPs), suggesting that STAT5 acts by altering ETP lineage commitment. Supporting this hypothesis, STAT5 binds to the pax5 promoter in ETPs from STAT5b-CA mice and induces pax5, a master regulator of B cell development. Conversely, STAT5b-CA mice exhibit a decrease in the DN1b subset of ETPs, demonstrating that STAT5 activation inhibits early T cell differentiation or lineage commitment. On the basis of these findings, we propose that the observed expression of the IL-7R on common lymphoid progenitors, but not ETPs, results in differential STAT5 signaling within these distinct progenitor populations and thus helps ensure appropriate development of B cells and T cells in the bone marrow and thymic environments, respectively.

Ebf1orPax5haploinsufficiency synergizes with STAT5 activation to initiate acute lymphoblastic leukemia

“…Expression was analyzed using quantitative real-time PCR (qRT-PCR). Consistent with our previous observation (Goetz et al, 2005) progenitor B cells from Stat5b-CA mice show increased expression of Pax5 relative to wild-type progenitor B cells (Goetz et al, 2005; Fig. 5 A).…”

“…To determine if the leukemic cells were proliferating more rapidly than wild-type pro-B and pre-B cells, we injected mice displaying visible signs of leukemia with BrdU. In both Stat5b-CA restore B cell development to near normal levels (Goetz et al, 2005). We crossed Stat5b-CA x Pax5 +/ mice to IL-7r / mice to generate Stat5b-CA x Pax5 +/ x IL-7r +/ or Stat5b-CA x Pax5 +/ x IL-7r / mice.…”

Regulation of Lymphocyte Development by Cell-Type-Specific Interpretation of Notch Signals

“…Thus, the regulation of Jak levels represents another mechanism by which Notch mediates its selective inhibitory effect on B-cell development. Consistent with our findings, it has been shown that the expression of a constitutively active form of STAT5, which can bypass the need for activating cytokines and Jaks, increases the numbers of B cells in the thymus (11).…”

IL-2 Receptor β-Dependent STAT5 Activation Is Required for the Development of Foxp3+ Regulatory T Cells

“…For these studies, we made use of transgenic mice that express a constitutively active form of STAT5b (STAT5b-CA) (21,26,31). Expression of STAT5b-CA is regulated by a compound promoter element consisting of the lck proximal promoter with the E enhancer inserted into it.…”