The Multifaceted Regulation of Interleukin-15 Expression and the Role of This Cytokine in Nk Cell Differentiation and Host Response to Intracellular Pathogens

Ta, Waldmann; Tagaya, Yutaka

doi:10.1146/annurev.immunol.17.1.19

Cited by 665 publications

(606 citation statements)

References 143 publications

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“…Although IL-15 mRNA and small amounts of soluble IL-15 have been reported to be produced by in vitro cultured FDC (64), it is important to confirm the production of IL-15 by FDC at the protein level: IL-15 mRNA is almost ubiquitously expressed, and the production and secretion of protein are mainly controlled by complex and inefficient posttranslational mechanisms (33,34). Our data reveal that FDCs produce IL-15, as shown by the immunofluorescence staining of freshly isolated FDC clusters.…”

Section: Discussionmentioning

confidence: 99%

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Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form

Park

Yoon

Armitage

et al. 2004

The Journal of Immunology

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Factors that control the survival and proliferation of Ag-stimulated B cells within the germinal center (GC) are crucial for humoral immune responses with high affinity Abs against infectious agents. The follicular dendritic cell (FDC) is known as a key cellular component of the GC microenvironment for GC-B cell survival and proliferation. In this study, we report that IL-15 is produced by human FDC in vivo and by an FDC cell line, FDC/HK cells, in vitro. IL-15 is captured by IL-15Rα on the surface of FDC/HK cells. The surface IL-15 is functionally active and augments GC-B cell proliferation. Because GC-B cells have the signal-transducing components (IL-2/15Rβγ), but not a receptor for binding of soluble IL-15 (IL-15Rα), IL-15 signaling is possibly transduced by transpresentation from FDCs to GC-B cells via cell-cell contact. Together, these results suggest that IL-15 from FDC, in membrane-bound form, plays an important role in supporting GC-B cell proliferation, proposing a new target for immune modulation as well as treatment of B cell tumors of GC origin.

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Section: Discussionmentioning

confidence: 99%

“…IL-15 was identified originally as an IL-2-like T cell growth factor (31)(32)(33), and has similar biologic properties to IL-2 in vitro such as augmentation of T cell proliferation and activation (34). IL-15 mRNA is expressed ubiquitously by a large variety of tissues, but not primary T cells (32,35,36).…”

mentioning

confidence: 99%

Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form

Park

Yoon

Armitage

et al. 2004

The Journal of Immunology

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“…[5][6][7] Mice genetically lacking IL-2R␤, ␥c, IL-15R␣ or IL-15 were found not to have NK cells. 9,10,29 IL-15 has also been shown to stimulate NK cells to exhibit increased cytotoxicities.…”

Section: Effects Of In Vivo Depletion Of Nk Cells or Cd8 ϩ T Cells Onmentioning

confidence: 97%

“…[1][2][3][4][5][6][7] Memory phenotype CD8 ϩ T cells have also been shown to respond preferentially to exogenous IL-15. 8 Mice genetically lacking IL-15R␣ or IL-15 are deficient in NK cells, ␥␦ intestinal intraepithelial lymphocytes and memory phenotype CD8 ϩ T cells.…”

Section: Abstract: Tumor Immunity; Il-15; Ctl; Nk Cells; Transgenic mentioning

confidence: 99%

Overexpression of interleukin‐15 in vivo enhances antitumor activity against mhc class I‐negative and ‐positive malignant melanoma through augmented NK activity and cytotoxic T‐cell response

Yajima

Nishimura

Wajjwalku

et al. 2002

Intl Journal of Cancer

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Key words: tumor immunity; IL-15; CTL; NK cells; transgenic miceInterleukin (IL)-15 is a 15 kDa cytokine 1,2 that uses ␤ and ␥ chains of the IL-2 receptor for signal transduction and shares many of the biologic activities of IL-2, including the induction of proliferation of phytohemagglutinin-stimulated normal PBMCs, NK cells and B cells and the generation of CTLs and lymphokineactivated killer (LAK) cells in PBMCs in vitro. [1][2][3][4][5][6][7] Memory phenotype CD8 ϩ T cells have also been shown to respond preferentially to exogenous IL-15. 8 Mice genetically lacking IL-15R␣ or IL-15 are deficient in NK cells, ␥␦ intestinal intraepithelial lymphocytes and memory phenotype CD8 ϩ T cells. 9,10 We have recently constructed transgenic (Tg) mice that express IL-15 cDNA encoding a secretable isoform of the IL-15 precursor protein under the control of an MHC class I promoter and that have an increased number of memory CD8 ϩ T cells in the peripheral lymphoid tissues. 11,12 The overexpression of IL-15 augmented the in vivo Tc1 responses to OVA and Toxoplasma gondii infection. [13][14][15] Recent studies using IL-15 Tg mice have shown increases in NK and memory CD8 ϩ T cells in the peripheral lymphoid tissues. 7,16 Taken together, the results suggested that IL-15 is important for the development and maintenance of not only NK cells but also Ag-specific CD8 ϩ T cells. Several studies using a murine model have suggested that IL-15 has antitumor effects. 17,18 Daily administration of IL-15 prolonged the period of remission induced by cyclophosphamide in mice bearing rhabdomyosarcoma. 19 We previously reported that treatment with IL-15 in combination with IL-12 enhanced the activities of NK and CD8 ϩ T cells in thoracic exudate cells, providing strong antitumor activity against malignant pleurisy. 20 We have also reported that tumor therapy based on IL-15 gene transfection was effective against Meth A tumor cells. 21 Thus, IL-15 may exert antitumor effects and be useful for cancer immunotherapy.The expression levels of MHC class I on malignant cells are important for determining the malignant and metastatic capacities of tumor cells. 22 MHC class I-expressing melanoma cells contain Ags able to activate cytotoxic CD8 ϩ T cells, although they are weakly immunogenic. [23][24][25] On the other hand, MHC class I-deficient melanoma is not destroyed by cytotoxic CD8 ϩ T cells but is susceptible to NK cells, 26 most of which express MHC class I-specific inhibitory receptors. 27,28 We report here that the tumor growth of both MHC class I-expressing and -deficient B16 melanoma cells is severely retarded in IL-15 Tg mice. The relative contributions of NK cells and cytotoxic CD8 ϩ T cells to antitumor activity in IL-15 Tg mice differs between these 2 melanoma cells. Overexpression of IL-15 may shed new light on a therapeutic approach to control tumors expressing a various range of MHC class I glycoproteins. MATERIAL AND METHODS Transgenic gene construction and generation of transgenic miceIL-15 Tg mice with C57BL/6 background, which w...

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“…I nterleukin-15 uses ␤-chain of IL-2R and common cytokine receptor common ␥-chain (c␥) 3 for signal transduction and thus shares many properties of IL-2 despite having no sequence homology with IL-2 (1)(2)(3)(4)(5). In contrast to IL-2, which is produced mainly by activated T cells, IL-15 is produced by wide variety of cells, including the placenta, skeletal muscle, kidney, as well as intestinal epithelium (6,7).…”

mentioning

confidence: 99%

Enforced Expression of Bcl-2 Partially Restores Cell Numbers but Not Functions of TCRγδ Intestinal Intraepithelial T Lymphocytes in IL-15-Deficient Mice

Nakazato

Yamada

Yajima

et al. 2007

The Journal of Immunology

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IL-15 knockout (KO) mice have severely reduced numbers of TCRγδ intestinal intraepithelial T lymphocytes (i-IEL), suggesting requirements of IL-15 signaling in the development or maintenance of i-IEL. To determine an involvement of survival signals via Bcl-2 in IL-15-mediated homeostasis of TCRγδ i-IEL, we introduced a bcl-2 transgene into IL-15 KO mice. In situ apoptosis of TCRγδ i-IEL was decreased in Bcl-2 transgenic (Tg) × IL-15 KO mice compared with IL-15 KO mice. The enforced expression of Bcl-2 partially restored the numbers of TCRγδ i-IEL in IL-15 KO mice. However, effector functions of TCRγδ i-IEL, including cytokine production and cytotoxic activity, were not recovered in Bcl-2 Tg × IL-15 KO mice. Importantly, TCRγδ i-IEL in Bcl-2 Tg × IL-15 KO mice expressed a reduced level of eomesodermin, a transcription factor critical for effector functions of NK cells and CD8+ T cells. Similar to the case of TCRγδ i-IEL, enforced expression of Bcl-2 restored the numbers but not the functions of NK cells in IL-15 KO mice. These results suggest that Bcl-2-mediated survival signal is involved in the IL-15-mediated homeostasis of TCRγδ i-IEL and NK cells, but other signals from IL-15 are critical for inducing transcription factors, such as eomesodermin for their effector functions.

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The Multifaceted Regulation of Interleukin-15 Expression and the Role of This Cytokine in Nk Cell Differentiation and Host Response to Intracellular Pathogens

Cited by 665 publications

References 143 publications

Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form

Follicular Dendritic Cells Produce IL-15 That Enhances Germinal Center B Cell Proliferation in Membrane-Bound Form

Overexpression of interleukin‐15 in vivo enhances antitumor activity against mhc class I‐negative and ‐positive malignant melanoma through augmented NK activity and cytotoxic T‐cell response

Enforced Expression of Bcl-2 Partially Restores Cell Numbers but Not Functions of TCRγδ Intestinal Intraepithelial T Lymphocytes in IL-15-Deficient Mice

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