No abstract

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...

Since the cloning of interleukin (IL)-15 six years ago, there have been numerous studies examining the molecular and cellular biology of this cytokine. IL-15 and IL-2 have similar biologic properties in vitro, consistent with their shared receptor (R) signaling components (IL-2/15R␤␥ c ). However, specificity for IL-15 versus IL-2 is provided by unique private ␣-chain receptors that complete the IL-15R␣␤␥ and IL-2R␣␤␥ heterotrimeric high-affinity receptor complexes and thereby allow differential responsiveness depending on the ligand and highaffinity receptor expressed. Intriguingly, both IL-15 and IL-15R␣ transcripts have a much broader tissue distribution than IL-2/IL-2R␣. Further, multiple complex posttranscriptional regulatory mechanisms tightly control IL-15 expression. Thus, based upon complex regulation, as well as differential patterns of IL-15 and IL-15R␣ expression, it is likely that the critical in vivo functions of this receptor/ligand pair differ from those of IL-2 and IL-2R␣. Studies to date examining the biology of IL-15 have identified several key nonredundant roles, such as IL-15's importance during natural killer (NK) cell, NK-T cell, and intestinal intraepithelial lymphocyte development and function. A role for IL-15 during autoimmune processes such as rheumatoid arthritis and malignancies such as adult T-cell leukemia suggest that dysregulation of IL-15 may result in deleterious effects for the host. This review attempts to present concisely our current understanding of the cellular and molecular biology of IL-15, IL-15's role in human disease, and its potential clinical utility as a therapeutic agent or target. Molecular and cellular biology of interleukin 15 (IL-15)The discovery of IL-15 and its relation to IL-2 IL-15 was identified by 2 independent groups based upon its ability to stimulate proliferation of the IL-2-dependent CTLL-2 T-cell line in the presence of neutralizing anti-IL-2 antibodies. The activity within cell culture supernatants of the simian kidney epithelial cell line CV-1/EBNA was purified, molecularly cloned, and designated IL-15. 1 The activity identified in supernatants of the human T-cell leukemia virus-1 (HTLV-1) cell line, HuT-102, was purified and called 3 Scientists at the Immunex Corporation (Seattle, WA) isolated the 14-to 15-kd protein responsible for the CTLL proliferation within CV-1/ EBNA supernatants using anion-exchange and high-pressure liquid chromatography and sequenced the NH 2 -terminal residues. Degenerate oligonucleotide primers were generated from this partial protein sequence and were used to obtain the full-length simian IL-15 cDNA from a CV-1/EBNA cDNA library. With simian IL-15 cDNA as a probe, the full-length human IL-15 cDNA was cloned from the IMTLH bone marrow stromal cell line. 1 The IL-T protein identified by researchers at the National Institutes of Health within HuT-102 supernatants was later cloned and shown to be a chimera composed of the HTLV-1 long terminal repeat (LTR) and human IL-15. The HTLV-1 LTR was fused in frame immediatel...