IntroductionStat molecules are part of a highly conserved signaling pathway involved in cell-fate decisions like differentiation, proliferation, and apoptosis. [1][2][3] The cytokines interleukin-2, -4, and -7 (IL-2, IL-4, IL-7) regulate important aspects of lymphoid development and are strong activators of the transcription factors Stat5a and Stat5b. 4 The importance of Stat5a/b for lymphoid cells is also underlined by the fact that constitutively activated Stat5a/b are found in several forms of lymphoid leukemia in mice and humans. [5][6][7][8][9][10] Gene knockouts have greatly contributed to our knowledge about Stat transcription factors because they allowed exploration of their physiologic and pathophysiologic functions. 11 So far, all studies investigating the role of Stat5a/b in lymphopoiesis employed gene-targeted mice still expressing a residual protein corresponding to an N-terminal deletion mutant (Stat5a/b⌬N). 4,[12][13][14] Stat5a/b ⌬N/⌬N mice revealed surprisingly mild phenotypes in Band T-cell development and function.Characterization of the lymphoid compartment in Stat5a/b ⌬N/⌬N mice showed a modest reduction of B-and T-lymphoid-cell numbers accompanied by a complete lack of natural killer (NK) cells and CD4 ϩ CD25 ϩ suppressor T cells. 4,13,15 CD8 ϩ T cells were present but failed to respond to ␣-CD3 and IL-2. 4 Mature B-cell numbers in the periphery were also reduced due to an incomplete block at the early pro-B-cell developmental stage (Hardy fraction B). 13,14 Mice lacking IL-7 or the IL-7R have a block at the earliest step of B-cell development at Hardy fraction A and lack mature B-lymphoid cells in the periphery. 16,17 Notably, B-cell development can be rescued in these mice by forced expression of a constitutively active Stat5a/b mutant. 17 In addition, transgenic mice expressing a constitutively active Stat5b (Stat5b-CA) have increased numbers of pro-B cells. 14 As Stat5a/b are critical components in the signaling cascade downstream of IL-7R, abrogation of Stat5a/b was predicted to result in a dramatic phenotype. Thus, the observations in Stat5a/b ⌬N/⌬N mice were difficult to reconcile with the current understanding of signaling pathways controlling B-cell development.Moreover, Stat5a/b transcription factors have been shown to play an important role in various T-cell developmental decisions. Transgenic Stat5b-CA mice display increased numbers of CD8 ϩ but not CD4 ϩ T cells. 18 This implicates Stat5b as an important regulator of CD4 ϩ /CD8 ϩ lineage decision. Moreover, Stat5a/b DNA binding sites were found in regulatory regions of the T-cell receptor ␥ (TCR␥) gene locus, and Stat5b-CA mice displayed a modest increase in ␥␦ T-cell numbers. 18,19 In Stat5a/b ⌬N/⌬N mice, embryonic ␥␦ T-cell development was severely affected, but numbers were rapidly restored after birth. 20 Therefore, the relevance for Stat5a/b in adult ␥␦ thymopoiesis remained elusive. Another finding in Stat5a/b ⌬N/⌬N mice was striking. Among many substrates that are phosphorylated downstream of the Abelson oncogene, Stat5a...
We generated a transgenic mouse line that expresses the Cre recombinase under the control of the Ncr1 (p46) promoter. Cre-mediated recombination was tightly restricted to natural killer (NK) cells, as revealed by crossing Ncr1-iCreTg mice to the eGFP-LSLTg reporter strain. Ncr1-iCreTg mice were further used to study NK cell-specific functions of Stat5 (signal transducers and activators of transcription 5) by generating Stat5(f/f) Ncr1-iCreTg animals. Stat5(f/f) Ncr1-iCreTg mice were largely devoid of NK cells in peripheral lymphoid organs. In the bone marrow, NK-cell maturation was abrogated at the NK cell-precursor stage. Moreover, we found that in vitro deletion of Stat5 in interleukin 2-expanded NK cells was incompatible with NK-cell viability. In vivo assays confirmed the complete abrogation of NK cell-mediated tumor control against B16F10-melanoma cells. In contrast, T cell-mediated tumor surveillance against MC38-adenocarcinoma cells was undisturbed. In summary, the results of our study show that STAT5 has a cell-intrinsic role in NK-cell development and that Ncr1-iCreTg mice are a powerful novel tool with which to study NK-cell development, biology, and function.
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