Expression of type 1 (interferon gamma) and type 2 (interleukin-13, interleukin-5) cytokines at distinct stages of natural killer cell differentiation from progenitor cells.
To determine whether production of type 1 and type 2 cytokines defines discrete stages of natural killer (NK) cell differentiation, cytokine expression was analyzed in human NK cells generated in vitro in the presence of interleukin-15 (IL-15) and/or IL-2 from umbilical cord blood hematopoietic progenitors. Like peripheral NK cells, the CD161(+)/CD56(+) NK cells from these cultures contained a tumor necrosis factor alpha (TNF-alpha)(+)/granulocyte macrophage-colony-stimulating factor (GM-CSF)(+) subset, an interferon gamma (IFN-gamma)(+) subset, mostly included within the former, and very few IFN-gamma(-)/IL-13(+) cells. Instead, most immature CD161(+)/CD56(-) NK cells, detectable only in the cultures with IL-2, produced IL-13, TNF-alpha, and GM-CSF, but not IFN-gamma, and contained an IL-5(+) subset. In short-term cultures with IL-12 and feeder cells, a proportion of the immature cells acquired the ability to produce IFN-gamma. Part of these produced both IFN-gamma and IL-13, irrespective of induced CD56 expression. These in vitro data indicate that ability to produce the type 2 cytokines IL-13 and IL-5 defines CD161(+) NK cells at intermediate stages of differentiation, and is lost upon terminal functional differentiation, concomitant with acquired ability to produce IFN-gamma.
Loza
Matthew J
MJ
The Kimmel Cancer Center, Jefferson Medical College, Philadelphia, PA 19107, USA.
Zamai
Loris
L
Azzoni
Livio
L
Rosati
Emanuela
E
Perussia
Bice
B
D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D018793:Interleukin-13 / Q000096:biosynthesis; D019409:Interleukin-15 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015848:Interleukin-5 / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology; D007700:Kinetics; D018655:Lymphocyte Count; D017154:Stromal Cells; D014470:Umbilical Cord / Q000166:cytology
D016207:Cytokines; D018793:Interleukin-13; D019409:Interleukin-15; D007377:Interleukin-3; D015848:Interleukin-5; D007371:Interferon-gamma