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Impaired NK Cell Development in an IFN- Transgenic Mouse: Aberrantly Expressed IFN- Enhances Hematopoietic Stem Cell Apoptosis and Affects NK Cell Differentiation¹

Osamu Shimozato^*, John R. Ortaldo^*, Kristin L. Komschlies and Howard A. Young^2,*

^* Laboratory of Experimental Immunology, Center for Cancer Research, and Intramural Research Support Program, Science Applications International Corp.-Frederick, National Cancer Institute, Frederick, MD 21702

Aberrant expression of IFN- has been demonstrated to cause a wide variety of alterations in cell function and development. Previously we reported that constitutive expression of IFN- in bone marrow (BM) and thymus results in a total absence of B cells and a substantial decrease in the number of hematopoietic progenitor cells. In this study, we demonstrate a severe deficiency of NK1.1⁺CD3^- cells in this transgenic mouse model. Compared with normal control littermates, we found a pronounced reduction of NK cells in IFN- transgenic mouse spleen and liver despite maintenance of normal function. In addition, we observed a reduced number of BM cells in the IFN- transgenic mouse despite normal expression of hematopoietic growth factors in the BM. Interestingly, these cells were less responsive to stem cell factor (SCF) despite c-kit expression on hematopoietic stem cells (HSCs). We observed that addition of exogenous IFN- inhibited proliferation of HSCs and differentiation of NK precursors from HSCs in normal mice in response to SCF, IL-7, fms-like tyrosine kinase 3 ligand, and IL-15. Furthermore, we found that HSCs express the IFN-R subunit and undergo apoptosis in response to exogenous IFN-. Thus, we have demonstrated the occurrence of a severe deficiency of NK cells and lower numbers of BM cells in an IFN- transgenic mouse model. Furthermore, because exogenous IFN- affects the responsiveness to hematopoietic growth factors such as SCF in vitro, our results indicate that chronic expression of IFN- in vivo leads to widespread immune system defects, including alterations in NK cell differentiation.

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