Membrane-bound and soluble IL-15/IL-15Rα complexes display differential signaling and functions on human hematopoietic progenitors

Giron‐Michel, Julien; Giuliani, Massimo; Fogli, Manuela; Brouty‐Boyé, Danièle; Ferrini, Silvano; Baychelier, Florence; Eid, Pierre; Lebousse-Kerdilès, Caroline; Duralı, Deniz; Biassoni, Roberto; Charpentier, B; Vasquez, A. Cecilia; Chouaı̈b, Salem; Caignard, Anne; Moretta, Lorenzo; Azzarone, Bruno

doi:10.1182/blood-2005-01-0064

Cited by 75 publications

(74 citation statements)

References 43 publications

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“…Thus, injecting mice with a soluble (s) recombinant form of IL-15R␣ is reported to suppress NK cell proliferation (10) and certain T dependent immune responses in vivo (19)(20)(21)(22), and adding sIL-15R␣ in vitro can block the response of cell lines to IL-15 (20)(21)(22)(23)(24)(25). Despite these findings, there are other reports that sIL-15R␣ (26), and also a soluble sushi domain of IL-15R␣ (27), can enhance IL-15 responses of human cell lines.…”

mentioning

confidence: 69%

Converting IL-15 to a superagonist by binding to soluble IL-15Rα

Rubinstein

Kovář

Purton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

353

362

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IL-15 is normally not secreted in soluble form (8-10) but is held on the cell surface bound to a unique receptor, IL-15R␣, especially on dendritic cells (11-16). Cell-bound IL-15 then is presented in trans to T cells and NK cells and is recognized by the ␤␥ c receptor on these cells; such recognition maintains cell survival and intermittent proliferation.IL-15R␣ plays a mandatory role in presenting endogenous IL-15. Thus, like IL-15 -/-mice (1), IL-15R␣ -/-mice lack CD122 hi CD8 ϩ cells and NK cells (17), presumably because the IL-15 synthesized in IL-15R␣ -/-mice fails to leave the cytoplasm. Nevertheless, ␤␥ c ϩ cells can proliferate in response to a soluble recombinant form of IL-15 in the absence of IL-15R␣ (18). Moreover, under certain conditions, IL-15R␣ can be inhibitory. Thus, injecting mice with a soluble (s) recombinant form of IL-15R␣ is reported to suppress NK cell proliferation (10) and certain T dependent immune responses in vivo (19)(20)(21)(22), and adding sIL-15R␣ in vitro can block the response of cell lines to . Despite these findings, there are other reports that sIL-15R␣ (26), and also a soluble sushi domain of IL-15R␣ (27), can enhance IL-15 responses of human cell lines.In this paper, we investigated whether sIL-15R␣ can alter the response of normal mouse T cells to IL-15. As discussed below, IL-15 responses of CD8 ϩ T cells and NK cells are improved considerably by association with sIL-15R␣, both in vitro and in vivo. Results Stimulation by IL-15͞IL-15R␣ Complexes in Vitro.To examine whether the stimulatory function of soluble IL-15 is altered by binding to sIL-15R␣, purified MP CD44 hi CD122 hi CD8 ϩ cells were cultured in vitro with mouse IL-15 Ϯ mouse sIL-15R␣ covalently linked to the Fc portion of human IgG1 (sIL-15R␣-Fc). For IL-15 alone, half-maximal responses required Ϸ30 ng͞ml and responses were negligible with Ͻ10 ng͞ml (Fig. 1A and B). Here, the notable finding was that supplementing a low concentration of IL-15, e.g., 5 ng͞ml, with sIL-15R␣-Fc led to strong proliferative responses of MP CD8 ϩ cells as measured either by carboxyf luorescein diacetate succinimidyl ester (CFSE) dilution (Fig. 1 A) or by [ 3 H]thymidine incorporation (Fig. 1B). No proliferation occurred with sIL-15R␣-Fc alone (Fig. 1B), and the addition of sIL-15R␣-Fc failed to alter the response of MP CD8 ϩ cells to a different cytokine, IL-2 (data not shown). With IL-15, sIL-15R␣-Fc did not appear to act by enhancing the half-life of IL-15 in vitro (Fig. 6, which is published as supporting information on the PNAS web site).With a limiting concentration of cytokine, IL-15 responses were improved generally by 6-to 9-fold by the addition of sIL-15R␣-Fc. Adding sIL-15R␣-Fc also considerably improved the IL-15 response of CD122 hi NK cells (Fig. 1C) but was relatively ineffective on MP (CD44 hi ) CD4 ϩ cells, which express intermediate levels of CD122 (Fig. 1C). Unexpectedly, sIL-15R␣-Fc plus IL-15 led to significant proliferation of typical naïve CD44 lo CD122 lo CD8 ϩ cells, although only with high concentrations o...

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mentioning

confidence: 69%

Converting IL-15 to a superagonist by binding to soluble IL-15Rα

Rubinstein

Kovář

Purton

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

353

362

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“…22,23 IL-15 gene is expressed in several tissues, and IL-15 can be either secreted in low amounts or displayed as a membrane-bound cytokine by several cell types. [24][25][26][27][28] Therefore IL-15 is considered a microenvironmental factor, which supports lymphoid cell homeostasis and survival. [29][30][31] IL-15 is a growth or survival factor not only for CLL cells 13 but also for cells of other lymphoid neoplasias, 32-34 at least in vitro.…”

Section: Introductionmentioning

confidence: 99%

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

Totero

Meazza

Capaia

et al. 2008

Blood

Self Cite

108

103

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The clonal expansion of chronic lymphocytic leukemia (CLL) cells requires the interaction with the microenvironment and is under the control of several cytokines. Here, we investigated the effect of IL-15 and IL-21, which are closely related to IL-2 and share the usage of the common ␥ chain and of its JAK3-associated pathway. We found remarkable differences in the signal transduction pathways activated by these cytokines, which determined different responses in CLL cells. IL-15 caused cell proliferation and pre- IntroductionChronic lymphocytic leukemia (CLL), the most common leukemia in adults, is characterized by the progressive accumulation of CD5 ϩ neoplastic B cells, 1-3 which results from a dynamic balance between cell death and proliferation. 3,4 The finding that purified CLL cells do not proliferate and tend to undergo spontaneous apoptosis in vitro suggests that factors inducing CLL cell survival and proliferation might be present in the microenvironment of lymphoid organs or of the bone marrow. 5,6 Several cytokines such as the TNF family members BAFF and APRIL, 7,8 the chemokine SDF-1, 9,10 and interleukin-2 (IL-2) 11,12 and IL-15 13 stimulate CLL cell proliferation and/or survival in vitro. IL-2 and IL-15 share the usage of the IL-2R␤ (CD122) and of the common ␥ chain (␥ c ; CD132) 14,15 and thus have similar functional effects on IL-2R␤/␥ c ϩ cells. 16,17 The IL-2R␤ and ␥ c chains signal through the JAK1 and JAK3 tyrosine kinases, which activate downstream STAT pathways. 18,19 In addition to the IL-2R␤/␥ c complex, specific 21 molecules are required for high-affinity binding of each cytokine. Unlike IL-2R␣, IL-15R␣ is a high-affinity receptor also when expressed as an isolated chain, and is present on both lymphoid and nonlymphoid cell types. 20,21 IL-15R␣ is crucial for IL-15 activity, since both IL-15-and IL-15R␣-deficient mice display similar defects in the development of natural killer (NK) cells, of intraepithelial T lymphocytes, and of CD8 ϩ memory-type T cells. 22,23 IL-15 gene is expressed in several tissues, and IL-15 can be either secreted in low amounts or displayed as a membrane-bound cytokine by several cell types. [24][25][26][27][28] Therefore IL-15 is considered a microenvironmental factor, which supports lymphoid cell homeostasis and survival. 29-31 IL-15 is a growth or survival factor not only for CLL cells 13 but also for cells of other lymphoid neoplasias, 32-34 at least in vitro. Moreover, in IL-15-transgenic mice, IL-15 overexpression induces fatal T or NK lymphoproliferative disorders. 35 We and others recently demonstrated that IL-21, the last identified member of the IL-2 family, 36-38 is unable to trigger CLL cell proliferation, but rather induces their apoptosis. 39,40 This effect is potentiated by cell activation with CD40L, 39 with CpG synthetic oligonucleotides, or by BCR cross-linking. 40 IL-21 induces the JAK1 and JAK3 and the STAT1, STAT3, and STAT5 tyrosine phosphorylation in CLL B cells. 39 Similar early signaling events are also activated by IL-21, IL-2, or IL-1...

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“…3,4 Among these, interleukin-15 (IL-15) displays a broad spectrum of biologic activities, not only in mature immune cells, linking innate and acquired immunity, but also in the growth and survival of immature hematopoietic cells. [5][6][7] In addition to these physiological features in normal hematopoiesis, IL-15 has been proposed to promote pathogenesis of leukemic cells. 8,9 Recently, the powerful antiapoptotic properties of IL-15 have been suggested to confer a selective growth advantage to neoplastic cells promoting tumor cell growth, expansion, and organ infiltration of malignancies.…”

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confidence: 99%

“…8,9 Recently, the powerful antiapoptotic properties of IL-15 have been suggested to confer a selective growth advantage to neoplastic cells promoting tumor cell growth, expansion, and organ infiltration of malignancies. 3,[7][8][9][10] Concerning the clinical relevance of IL-15 in hematopoietic malignancies, elevated IL-15 levels have been shown to affect the initial response to therapy and were associated with malignant transformation, including organ infiltration and disease progression, such as relapse. 3,[10][11][12][13] In adult ALL, clinical studies have defined immunophenotype and molecular genetic markers, as well as the duration of first remission, as the most significant independent prognostic determinants.…”

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confidence: 99%

Expression of interleukin 15 in primary adult acute lymphoblastic leukemia

Fischer²,

Gökbuget

et al. 2009

Cancer

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BACKGROUND:Interleukin‐15 (IL‐15) has been associated with the growth, survival and biological behavior of leukemic cells and response to therapy. We determined the expression of IL‐15 in lymphoblasts and evaluated its potential impact on the outcome in adult acute lymphoblastic leukemia (ALL).METHODS:Between June 1999 and June 2006, ALL samples were collected from 87 adult patients before initiation of antineoplastic therapy. These patients were enrolled in the German Multicenter Acute Lymphoblastic Leukemia June 1999 and July 2003 study trials. The expression of IL‐15 in leukemic cells was analyzed by real‐time polymerase chain reaction.RESULTS:The expression of IL‐15 correlated with the immunophenotype: T‐lineage ALL had a more than 4‐fold higher IL‐15 mRNA expression as compared with B‐cell precursor (BCP)‐ALL (P < .001). Patients with BCR‐ABL+‐BCP‐ALL had lower IL‐15 expression compared with BCR‐ABL−‐BCP‐ALL (P = .041). Furthermore, higher expression of IL‐15 was associated with mediastinal (P = .001) and lymph node infiltration (P = .051), but not with hepatomegaly and splenomegaly. Notably, high IL‐15 expression in BCP‐ALL was associated with an inferior relapse‐free survival (RFS) at 5 years (0.17 ± 0.13 vs 0.47 ± 0.13) (P = .008), but there was no impact on overall survival (P = .249).CONCLUSIONS:Differential expression of IL‐15 in adult ALL at diagnosis was associated with clinical features and outcome, in particular, RFS. It remains to be evaluated whether IL‐15 might be a relevant therapy target, or might be used for risk stratification. Cancer 2010. © 2010 American Cancer Society.

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Membrane-bound and soluble IL-15/IL-15Rα complexes display differential signaling and functions on human hematopoietic progenitors

Cited by 75 publications

References 43 publications

Converting IL-15 to a superagonist by binding to soluble IL-15Rα

Converting IL-15 to a superagonist by binding to soluble IL-15Rα

The opposite effects of IL-15 and IL-21 on CLL B cells correlate with differential activation of the JAK/STAT and ERK1/2 pathways

Expression of interleukin 15 in primary adult acute lymphoblastic leukemia

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