The role of STAT5 in hematolymphoid development in vivo

Hematolymphoid development is regulated by multiple systems delivering signals from physiologic inputs. Among these are cytokines delivering signals to target cells through activation of cognate cell surface receptors. The role of specific signaling molecules utilized by cytokines in hematolymphoid development in the context of the organism has not been fully elucidated.; We hypothesized that Signal Transducer and Activator of Transcription 5 (STAT5), a signal transduction molecule activated by many cytokine receptors in hematopoiesis, would play a significant role in the efficient performance of this process in vivo. Using STAT5A/5B-deficient mice, we found this molecule to be critical in maintaining wild-type levels of multiple blood lineages at steady-state, due to cell-autonomous defects in hematopoietic progenitors, perhaps related to decreased survival of these cells.; Examination of STAT5A/5B-deficient mice expressing a Bcl-2 transgene revealed that ectopic expression of Bcl-2 was not sufficient to rescue all hematopoietic defects seen in STAT5A/5B-deficient mice, indicating alternate biological roles of STAT5 in early hematopoietic progenitors.; Suspecting that defects in cells other than hematopoietic progenitors were contributing to hematopoietic defects in these mice, we found that loss of tolerance in these mice leads to an autoimmune pathology affecting multiple processes including hematolymphoid development. STAT5's toleragenic role may be contributing to the homeostatic survival of CD4+/CD25 + regulatory T cells. We were also able to show that hematopoietic defects in STAT5A/5B−/− mice could be rescued with transplant of wild-type bone marrow, indicating that STAT5A/5B-deficiency in non-hematopoietic tissue did not adversely affect hematolymphoid development at steady-state.; Finally, we wished to explore the role of STAT5 as a molecular effector of IL-7 receptor activation in normal lymphocyte development. Using mice expressing an IL-7 transgene, we found a STAT5-dependent role for this cytokine in the preferential development of CD8+ T-cells. In addition, we found that heterozygosity of STAT5 was able to provide protection from the IL-7-induced lymphomas found in these Tg IL-7 mice.; Taken together, these discoveries will add significantly to our understanding of cytokine-dependent signal transduction, in particular that of STAT5, in hematolymphoid development in vivo. In addition, these findings will contribute to our understanding of this molecule as a therapeutic target.