Potential mechanisms of human natural killer cell expansion in vivo during low-dose IL-2 therapy.
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/G(2)/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.
Fehniger
T A
TA
Department of Medicine, Division of Hematology/Oncology. Division of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
Bluman
E M
EM
Porter
M M
MM
Mrózek
E
E
Cooper
M A
MA
VanDeusen
J B
JB
Frankel
S R
SR
Stock
W
W
Caligiuri
M A
MA
D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D019002:CD56 Antigen / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology
D018952:Antigens, CD34; D019002:CD56 Antigen; D007376:Interleukin-2; D011994:Recombinant Proteins