Stat5 Is Required for IL-2-Induced Cell Cycle Progression of Peripheral T Cells

Abstract

Many cytokines activate two highly homologous Stat proteins, 5a and 5b. Mice deficient in both genes lack all growth hormone and prolactin functions but retain functions associated with cytokines such as erythropoietin. Here, we demonstrate that, while lymphoid development is normal, Stat5a/b mutant peripheral T cells are profoundly deficient in proliferation and fail to undergo cell cycle progression or to express genes controlling cell cycle progression. In addition, the mice lack NK cells, develop splenomegaly, and have T cells with an activated phenotype, phenotypes seen in IL-2 receptor beta chain-deficient mice. These phenotypes are not seen in mice lacking Stat5a or Stat5b alone. The results demonstrate that the Stat5 proteins, redundantly, are essential mediators of IL-2 signaling in T cells.

IL-2 and long-term T cell activation induce physical and functional interaction between STAT5 and ETS transcription factors in human T cells

“…Presence of Stat5 in the C2p inducible complex is in line with one of its roles evidenced in mice defective for Stat5 expression (Feldman et al, 1997;Imada et al, 1998;Moriggl et al, 1999;Nakajima et al, 1997;Teglund et al, 1998;Udy et al, 1997). The phenotype of peripheral T cells from Stat5a/b-de®cient mice, opposed to single knock-out, revealed a crucial and interchangeable role for these proteins in IL-2 signaling (Moriggl et al, 1999).…”

“…The phenotype of peripheral T cells from Stat5a/b-de®cient mice, opposed to single knock-out, revealed a crucial and interchangeable role for these proteins in IL-2 signaling (Moriggl et al, 1999). Mature T cells of these mice exhibited a dramatic decrease in proliferative response triggered by anti-CD3 and IL-2.…”

“…Consistent with a role of both Stat5 proteins in the transcriptional activation of the CD25/IL-2Ra gene, expression of the inducible chain of IL-2 was not maintained on lymphocytes of Stat5a/ b-de®cient mice in presence of IL-2 (Moriggl et al, 1999). PRRIII is a composite region composed of both consensus and non-consensus GAS motifs (GASd and GASp), two distinct Ets binding sites (EBSd and EBSp) and one GATA motif.…”

Chemokines: attractive mediators of the immune response

“…Indeed, a constitutively active form of Stat3 is able to transform cells, indicating a critical role for Stat3 in regulating cell growth and differentiation [53]. Stat5 is required for cell cycle progression facilitated by IL-2, since T cells derived from mice lacking Stat5a, Stat5b, or both, exhibit impaired growth responses to IL-2 mediated costimulation [54][55][56]. Indeed, activation of the TCR will result in Stat5 phosphorylation-activation and a subsequent proliferative response by the T cell [57].…”

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

“…Nonetheless, the phenotypes of these mice demonstrated an essential though often redundant role for the two Stat5 proteins in a spectrum of physiological responses associated with growth hormone and prolactin signaling; and yet, the responses to most Stat5-activating cytokines, including erythropoietin, were largely una ected, except possibly during fetal development (Socolovsky et al, 1999). Impaired peripheral T lymphocyte proliferation was also observed in Stat5a,b7/7 mice, but this phenotype was ascribed to fundamental defects in cell cycle entry rather than to decreased IL2 receptor expression (Moriggl et al, 1999). While lymphopoiesis was normal, T cells from Stat5 doubly-de®cient mice were profoundly impaired in proliferation and failed to undergo cell cycle progression or to express some of the genes controlling cell cycle progression.…”