Identification of an Interleukin-15α Receptor-binding Site on Human Interleukin-15

Bernard, Jérôme; Harb, Catherine; Mortier, Erwan; Quéméner, Agnès; Meloen, Rob H.; Vermot-Desroches, Claudine; Wijdeness, John; Dijken, Peter van; Grötzinger, Joachim; Slootstra, Jerry W.; Plet, Ariane; Jacques, Yannick

doi:10.1074/jbc.m312458200

Cited by 54 publications

(91 citation statements)

References 51 publications

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“…Indeed, the affinity of IL-15 for IL-15R␣ or for IL-15R␤␥ c is higher than the affinity of KIRs for MHC class I molecules (K d Ϸ0.1-1nM and K d Ϸ7-100M, respectively). [37][38][39][40][41] Therefore, IL-15R␣ might be kept at the synapse by the high-avidity interaction of IL-15 trans-presentation by IL-15R␣ to IL-15R␤␥ c . In contrast, the low affinity interaction of MHC class I molecules with KIRs could require enrichment at the synapse by fence-like partitioning of the f-actin based membrane skeleton (MSK) at the synapse.…”

Section: Discussionmentioning

confidence: 99%

Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

Silva

Graf

Münz

2011

Blood

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IntroductionDendritic cells (DCs) are key players in the immune system as they bridge innate and adaptive immunity. 1 In their immature form, DCs reside as sentinels for pathogens and stress signals in almost all organs of the human body. On interaction with so-called maturation stimuli, DCs migrate at increased frequency to secondary lymphoid organs for the initiation of immune responses. 2 DC maturation leads also to the up-regulation of antigen presentation on MHC molecules, 3 of chemokine receptors and of costimulatory molecules, 4 as well as to the release of cytokines. 5,6 In secondary lymphoid tissues, mature DCs are able to alert and activate cells of the adaptive immune system, like T cells, and also of the innate immune system, like natural killer (NK) cells. [7][8][9] Indeed, NK-cell activation by DCs is required for many immune responses. [10][11][12][13][14][15] On interaction with mature DCs and the cytokines that they produce, resting NK cells, preferentially those resident in secondary lymphoid organs, secrete IFN-␥, TNF, and GM-CSF. This effect is mostly mediated via IL-12 and IL-18 production by DCs. 7,[16][17][18] Moreover, cytokines secreted by DC-activated NK cells induce further maturation of DCs in secondary lymphoid tissues, prompting them to efficiently stimulate CTL responses. Furthermore, type I IFN of mature DCs up-regulates cytotoxicity of NK cells for powerful anti-tumor 19 and anti-viral immune responses. 17,20 Finally, the interaction with mature DCs also elicits resting NK-cell priming, 10 survival 21,22 and proliferation, 7 via DC produced IL-15. Thus, mature DCs secrete several cytokines that stimulate distinct NK-cell functions.Up-regulation of NK-cell cytotoxicity through this interaction could lead to the killing of DCs, thereby compromising the priming of efficient adaptive immune control by these antigen presenting cells. To minimize DC lysis, mature DCs have developed mechanisms that prevent the cytotoxic effect of activated lymphocytes, while immature DCs can be edited by activated NK cells via NKp30 mediated recognition. 3 Among these protective mechanisms against cell-mediated cytotoxicity, mature DCs express members of the serpin-family of serin protease-inhibitors that prevent apoptosis induction by granzyme B. 23 Moreover, maturation leads to the up-regulation of MHC class I molecules on the surface of DCs. MHC class I molecules interact with inhibitory receptors on the NK-cell surface, controlling the activation of these lymphocytes. 3 Thus, a balance between activating and inhibitory signals seems to exist at the immunologic synapse between mature DCs and resting NK cells. 21 In this way, resting NK cells can be efficiently activated by DCs and, at the same time, mature DCs are protected from being killed.To characterize the development of the regulatory synapse between mature DCs and resting NK cells, we describe here the kinetics of distribution of cytoskeletal elements, as well as activating and inhibitory molecules in conjugates of mature DCs with resting NK c...

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Section: Discussionmentioning

confidence: 99%

Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

Silva

Graf

Münz

2011

Blood

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“…Third, there are well-conserved residues of defined function in the multiple alignment of the IL-15 sequences (Fig. 2), including four highly conserved cysteine residues, which have been postulated in mammals to be important in the formation of correctly folded molecules (13), and one of the two IL-15R␣ binding sites identified in the human IL-15 molecule (57). Fourth, all the IL-15 proteins, including the trout IL-15, are encoded by six exons, and all the introns in the coding region are phase 0 except the second one that is phase I (Table II).…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Characterization of IL-15 in Rainbow TroutOncorhynchus mykiss:A Potent Inducer of IFN-γ Expression in Spleen Leukocytes

Wang

Holland

Carrington

et al. 2007

The Journal of Immunology

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IL-15 is a member of the common γ-chain family of cytokines that possess a heterogeneous repertoire of activities on various cells of the immune system. We report here the first functional characterization of a fish IL-15 in rainbow trout. The trout IL-15 gene is 6-kb long and contains six exons and five introns that transcribe into a 1.2-kb mRNA containing seven out-of-frame AUG initiation codons and translate into a 193-aa peptide. Potential sites for transcriptional activators and repressors have been identified in the trout IL-15 gene. Like IL-15 from other species, trout IL-15 is closely linked to an INPP4B gene, but there is also a BCL10 gene located between the IL-15 and INPP4B genes. Three alternative splicing variants of the trout IL-15 gene have also been identified and their expression in vivo was studied. Trout IL-15 expression is present in all the tissues and cell lines studied. Recombinant trout IFN-γ selectively increased IL-15 expression but had little effect on other cytokines such as IL-1β and IL-11. Recombinant trout IL-15 preferentially stimulated splenic leukocytes from healthy fish, where it induced a large increase in IFN-γ expression, with little, if any, effect on IL-1β expression. This effect was quite long-lived, and was still apparent 24 h poststimulation. Although the exact cell types being affected have still to be determined, it is clear that once produced IL-15 will have a profound affect on the ability of the fish immune system to activate antimicrobial defenses and genes induced themselves by IFN-γ.

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“…The scFv was incubated with the peptides and specific binding detected using an anti-hexahistidine antibody. Binding signals were measured in a 384-well ELISA reader (19,20).…”

Section: Epitope Determination Using Linear Peptide Mappingmentioning

confidence: 99%

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

Friedrich

Henn

Raum

et al. 2014

Molecular Cancer Therapeutics

Self Cite

117

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There is high demand for novel therapeutic options for patients with acute myelogenous leukemia (AML). One possible approach is the bispecific T-cell-engaging (BiTE, a registered trademark of Amgen) antibody AMG 330 with dual specificity for CD3 and the sialic acid-binding lectin CD33 (SIGLEC-3), which is frequently expressed on the surface of AML blasts and leukemic stem cells. AMG 330 binds with low nanomolar affinity to CD33 and CD3e of both human and cynomolgus monkey origin. Eleven human AML cell lines expressing between 14,400 and 56,700 CD33 molecules per cell were all potently lysed with EC 50 values ranging between 0.4 pmol/L and 3 pmol/L (18-149 pg/mL) by previously resting, AMG 330-redirected T cells. Complete lysis was achieved after 40 hours of incubation. In the presence of AML cells, AMG 330 specifically induced expression of CD69 and CD25 as well as release of IFN-g, TNF, interleukin (IL)-2, IL-10, and IL-6. Ex vivo, AMG 330 mediated autologous depletion of CD33-positive cells from cynomolgous monkey bone marrow aspirates. Soluble CD33 at concentrations found in bone marrow of patients with AML did not significantly affect activities of AMG 330. Neoexpression of CD33 on newly activated T cells was negligible as it was limited to 6% of T cells in only three out of ten human donors tested. Daily intravenous administration with as low as 0.002 mg/kg AMG 330 significantly prolonged survival of immunodeficient mice adoptively transferred with human MOLM-13 AML cells and human T cells. AMG 330 warrants further development as a potential therapy for AML. Mol Cancer Ther; 13(6); 1549-57. Ó2014 AACR.

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Identification of an Interleukin-15α Receptor-binding Site on Human Interleukin-15

Abstract: To identify the epitopes in human interleukin-15 (IL-15

Cited by 54 publications

References 51 publications

Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

Cytoskeletal stabilization of inhibitory interactions in immunologic synapses of mature human dendritic cells with natural killer cells

Molecular and Functional Characterization of IL-15 in Rainbow TroutOncorhynchus mykiss:A Potent Inducer of IFN-γ Expression in Spleen Leukocytes

Preclinical Characterization of AMG 330, a CD3/CD33-Bispecific T-Cell–Engaging Antibody with Potential for Treatment of Acute Myelogenous Leukemia

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