Potential mechanisms of human natural killer cell expansion in vivo during low-dose IL-2 therapy
Todd A. Fehniger, … , Wendy Stock, Michael A. Caligiuri
Todd A. Fehniger, … , Wendy Stock, Michael A. Caligiuri
Published January 1, 2000
Citation Information: J Clin Invest. 2000;106(1):117-124. https://doi.org/10.1172/JCI6218.
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Potential mechanisms of human natural killer cell expansion in vivo during low-dose IL-2 therapy

Abstract

The continuous, in vivo infusion of low-dose IL-2 selectively expands the absolute number of human natural killer (NK) cells after 4–6 weeks of therapy. The mechanism responsible for this expansion is unknown and was examined in this study. NK cells cultured at low concentrations of IL-2, comparable to those found during in vivo therapy, proliferate for 6 days and then exit the cell cycle. However, NK cells in vivo did not traverse the S/G2/M phase of the cell cycle during low-dose IL-2 therapy. Low concentrations of IL-2 delay programmed cell death of NK cells but have the same effect on resting T cells that do not expand in vivo. When CD34+ bone marrow hematopoietic progenitor cells are cultured for 21 days with low concentrations of IL-2, they differentiate into CD56+CD3− NK cells, not T cells. Thus, the selective expansion of human NK cells during continuous in vivo infusion of low-dose IL-2 likely results from enhanced NK-cell differentiation from bone marrow progenitors, combined with an IL-2–dependent delay in NK-cell death, rather than proliferation of mature NK cells in the periphery.

Authors

Todd A. Fehniger, Eric M. Bluman, Michelle M. Porter, Ewa Mrózek, Megan A. Cooper, Jeffrey B. VanDeusen, Stanley R. Frankel, Wendy Stock, Michael A. Caligiuri

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Figure 2

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Correlation of apoptosis and proliferation of IL-2–stimulated CD56bright...
Correlation of apoptosis and proliferation of IL-2–stimulated CD56bright NK cells as evaluated by PI/BrdU assay. Shown are representative contour plots of sorted CD56bright NK cells cultured in the absence (a) or presence (b) of 100 pM IL-2 for 6 days and assayed as described in Methods. BrdU incorporation (proliferative activity) is measured along the abscissa (FITC fluorescence). PI fluorescent intensity (DNA content) is measured along the ordinate (red fluorescence). Cells that have undergone apoptosis show a hypodiploid complement of DNA and fall below the dashed horizontal divider. Normal (viable) diploid cells are found between the dashed and solid horizontal lines. In the absence of IL-2 (a), there is no evidence of BrdU incorporation, and the vast majority of CD56bright NK cells are found within the hypodiploid fraction by day 6. In the presence of IL-2 (b), a fraction of cells proliferate, incorporate BrdU, and are therefore seen to the right of the vertical divider. Apoptosis has only occurred within the nondividing fraction of cells (left, below dashed line). This is representative of three independent experiments with similar results.