During the innate immune response to infection, monocyte-derived cytokines (monokines), stimulate natural killer (NK) cells to produce immunoregulatory cytokines that are important to the host's early defense. Human NK cell subsets can be distinguished by CD56 surface density expression (ie, CD56 bright and CD56 dim ). In this report, it is shown that CD56 bright NK cells produce significantly greater levels of interferon-␥, tumor necrosis factor-␤, granulocyte macrophage-colony-stimulating factor, IL-10, and IL-13 protein in response to monokine stimulation than do CD56 dim NK cells, which produce negligible amounts of these cytokines. Further, qualitative differences in CD56 bright NK-derived cytokines are shown to be dependent on the specific monokines present. For example, the monokine IL-15 appears to be required for type 2 cytokine produc- IntroductionNatural killer (NK) cells are innate immune effectors that produce immunoregulatory cytokines, such as interferon (IFN)-␥ and granulocyte macrophage-colony-stimulating factor GM-CSF, critical to early host defense against a variety of viral, bacterial, and parasitic pathogens. [1][2][3][4] Human NK cells comprise approximately 10% of all peripheral blood lymphocytes and are characterized phenotypically by the presence of CD56 and the lack of CD3. 1 There are 2 distinct subsets of human NK cells identified by cell surface density of CD56. The majority (approximately 90%) of human NK cells are CD56 dim and express high levels of Fc␥RIII (CD16), whereas a minority (approximately 10%) are CD56 bright and CD16 dim/neg . 5 CD56 bright NK cells constitutively express the high-and intermediate-affinity IL-2 receptors and expand in vitro and in vivo in response to low (picomolar) doses of IL-2. [6][7][8] These NK cells also express the c-kit receptor tyrosine kinase whose ligand enhances IL-2-induced proliferation. 9,10 In contrast, resting CD56 dim NK cells express only the intermediate affinity IL-2 receptor, are c-kit neg , and proliferate weakly in response to high doses of IL-2 (1 to 10 nM) in vitro, even after induction of the high-affinity IL-2 receptor. 6,7 Resting CD56 dim NK cells are more cytotoxic against NK-sensitive targets than CD56 bright NK cells. 11 However, after activation with IL-2 or IL-12, CD56 bright cells exhibit similar or enhanced cytotoxicity against NK targets compared to CD56 dim cells. [11][12][13] NK cell subsets have differential natural killer receptor (NKR) NK cells constitutively express receptors for monocyte-derived cytokines (monokines) and produce critical cytokines, such as IFN-␥, in response to monokine stimulation. [17][18][19][20] In the current study we examine CD56 bright and CD56 dim NK cell production of multiple cytokines-including IFN-␥, tumor necrosis factor (TNF)-␤, IL-10, IL-13, TNF-␣, and GM-CSF-in response to stimulation with monokines. We show that CD56 bright NK cells are the primary population responsible for NK cell cytokine production in response to monokines. These data support a model whereby CD56 bright a...

No abstract

No abstract