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

Abstract

IntroductionNatural killer (NK) cells mediate the early, nonadaptive, responses against virus-, intracellular bacteria-, and parasite-infected cells, 1 and modulate the activity of other effector cells of the adaptive and innate systems of defense. In the mouse, interleukin-12 (IL-12)-induced interferon gamma (IFN-␥) production by mature NK cells 2,3 directs the development of Ag-specific cell-mediated responses to intracellular pathogens, controlling Th1 cell differentiation 4 (reviewed in Trinchieri and Scott 5 and Coffman et al 6 ). NK cells participate in the regulation of myeloid hematopoiesis, 7 and activation of myeloid 8 and monocytic cells (reviewed in Trinchieri et al 9 ) via production of granulocyte macrophage-colonystimulating factor (GM-CSF), IL-3, IFN-␥ and tumor necrosis factor alpha (TNF-␣). 10-14 They have also been proposed to participate in the regulation of humoral immune responses, 15,16 and to play a significant role in the asthma-associated eosinophilia 17,18 via IL-5 production, and possibly other factors. A minor subset or subsets of IL-13 19 and of IL-5 producing NK cells exists in adult peripheral and umbilical cord blood. 20,21 Whether combinations of different cytokines are produced by NK cells at distinct stages of differentiation or by distinct mature NK cell subsets remains to be established.NK cell differentiation is controlled by cytokines produced in an intact bone marrow microenvironment 22,23 (reviewed in Sivakumar et al 24 ). In the murine system, these include Flt-3 ligand 1 (Flt3-L), 25 c-kit ligand (stem cell factor, SCF), 25,27 that act, alone or together, on NK cells at different stages of differentiation. 25 Flt3-L and IL-15 sustain differentiation of human CD34 ϩ bone marrow cells to cells functionally and phenotypically similar to mature peripheral blood NK cells. [28][29][30] Produced by stromal and monocytic/myeloid cells, 31 they likely also act in vivo in physiologic conditions (reviewed in Carson and Calgiuri 32 ). Possible differential effects of these cytokines on NK cell differentiation have been analyzed only at very early developmental stages, 30,33,34 when NK lineage-specific markers are not yet identifiable.In rodents (mouse 35,36 and rat 37 ) and humans 38-42 IL-2 efficiently substitutes for IL-15 in vitro to support NK cell differentiation from CD34 ϩ or lineage negative (Lin Ϫ ) hematopoietic progenitor cells. We have reported an in vitro model of human NK cell differentiation involving coculture of umbilical cord blood Lin Ϫ hematopoietic progenitor cells with IL-2 and a murine stromal cell line expressing the membrane-bound form of SCF (mSCF). 21 Using this system, we established that expression of CD161 in the absence of other mature NK cell markers defines NK cells at a relatively immature stage of differentiation. CD161 ϩ /CD56 Ϫ NK cells mediate TRAIL-L-mediated, but not FasL-mediated or granule exocytosis-mediated cytotoxicity, 43 and do not express IFN-␥ upon stimulation. 21 However, in culture conditions including IL-12 and feeder cells, a pr...

Interleukin‐15 prevents concanavalin A‐induced liver injury in mice via NKT cell‐dependent mechanism†

“…5A showed liver hepatitis was completely inhibited in anti-IL-4 Ab-treated mice while partly inhibited in IL-5-depleted mice because IL-4 also induced an increase in the expression of granzyme B and FasL on NKT cells. 7 Moreover, we and others 35,36 found NKT cells treated with IL-15 failed to produce IL-5. These best explain why IL-15-treated NKT cells may exert negative regulatory effects on eosinophils.…”

STAT6-Dependent Differentiation and Production of IL-5 and IL-13 in Murine NK2 Cells

“…However, human NK cells are known to produce type 2 cytokines as well, particularly when cultured with certain cytokines (3)(4)(5)(6)(7). NK1/NK2 terminology has been proposed in analogy to Th1/Th2 subsets of CD4 T cells (4).…”

IL-21 Induces the Functional Maturation of Murine NK Cells

“…Therefore, in vivo-stimulated NK cells responded with striking similarity to those treated with IL-21 in vitro. Ϫ/Ϫ bone marrow and spleen DX5 ϩ NK cells were cultured for 7 days with the indicated cytokine before being subjected to a standard 51 Cr release assay. Data are the mean of triplicate wells Ϯ SE.…”