Natural, Proteolytic Release of a Soluble Form of Human IL-15 Receptor α-Chain That Behaves as a Specific, High Affinity IL-15 Antagonist

Mortier, Erwan; Bernard, Jérôme; Plet, Ariane; Jacques, Yannick

doi:10.4049/jimmunol.173.3.1681

Cited by 123 publications

(130 citation statements)

References 44 publications

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…Once this site is occluded, by binding either to endogenous IL-15R␣ on cells in vivo or to IL-15R␣ attached to plastic in vitro, interaction with exogenous sIL-15R␣-Fc fails to occur, and there is no interference with presentation of IL-15 to T cells. This scenario does not explain why sIL-15R␣ can block the response of cell lines to IL-15 (20)(21)(22)(23)(24)(25). Here it may be relevant that these studies used human or simian IL-15, and not mouse IL-15 as in our study, which raises the possibility of distinct species differences in IL-15.…”

Section: Injecting Mice With Lps Is Known To Cause a Brief Increase Imentioning

confidence: 40%

“…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 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: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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...

show abstract

Section: Injecting Mice With Lps Is Known To Cause a Brief Increase Imentioning

confidence: 40%

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Binding of soluble IL-15Ra to soluble IL-15 led to competition with cell surface receptors inhibiting IL-15-mediated function (14). Later, complex formation of recombinant soluble IL-15 and IL-15Ra-Fc molecules was reported to enhance the bioactivity of IL-15, inducing proliferation of NK cells and memory T cells in vitro and in vivo (23,25).…”

Section: Discussionmentioning

confidence: 99%

“…case, soluble IL-15Ra might arise from proteolytic cleavage of the membrane form by metalloproteinases (14,15).…”

Section: Introductionmentioning

confidence: 99%

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

Kermer

Baum²,

Hornig³

et al. 2012

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Cytokines driving the immune response are powerful tools for cancer immunotherapy, but their application is generally limited by severe systemic toxicity. Targeted approaches by means of antibodycytokine fusion proteins might enable focus on the cytokine activity to the tumor site, thereby reducing unwanted side effects. Here, we investigated the possibility to improve the efficiency of interleukin (IL)-15 presentation in a targeted approach by the incorporation of an IL-15Ra chain fragment, mimicking physiologic trans-presentation. Therefore, an antibody cytokine fusion protein (scFv_RD_IL-15) composed of an antibody moiety targeting the tumor stromal fibroblast activation protein (FAP), an extended IL15Rasushi domain (RD) and IL-15 was generated, exhibiting antibody-mediated specific binding and cytokine activity in soluble and targeted form. Comparative analysis with a corresponding antibody fusion protein devoid of RD (scFv_IL-15) showed for scFv_RD_IL-15 in solution enhanced stimulatory activity on Mo7e (IL-15Rbg) cells and reduced proliferation response on CTLL-2 (IL-15Rabg) cells, while in FAPtargeted, that is, membrane-bound form, comparable proliferation of CTLL-2 (IL-15Rabg) cells was obtained. In addition, scFv_RD_IL-15 achieved in its soluble and target-bound form stronger proliferation and cytotoxicity on unstimulated and activated T cells, respectively. Furthermore, in vivo analysis in a lung metastasis tumor mouse model revealed a superior antitumor effect for scFv_RD_IL-15 in comparison with that obtained by an untargeted or RD missing version of IL-15 fusion protein. Thus, tumor-directed transpresentation of IL-15 in association with RD in form of an antibody fusion protein seems to be a promising approach to further improve the antitumor effect of IL-15.

show abstract

“…For example, natural killer (NK) cells require IL-15 to be trans-presented by both DCs and macrophages while central memory CD8 1 T cells require DC-derived IL-15. 7,8 Moreover, cell-bound IL-15 can act in cis on producer cells 9 and the IL-15: IL-15Ra complex can be released by proteolytic cleavage, 10 indicating further complexity in IL-15 signalling.…”

Section: Introductionmentioning

confidence: 99%

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

et al. 2016

View full text Add to dashboard Cite

Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is required for the survival and activation of memory CD8 1 T cells, natural killer (NK) cells, innate lymphoid cells, macrophages and dendritic cells. IL-15 is implicated in the pathogenesis of various autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, psoriasis and autoimmune type 1 diabetes (T1D). IL-15 receptor (IL-15R) consists of a specific a chain, the b chain that is shared with IL-2R and the common c chain. IL-15 is unique in the manner in which it binds and signals through its receptor subunits. IL-15 that is complexed with IL-15Ra binds to the bc receptor complex present on the responding cell to mediate its biological effects through a process referred to as trans-presentation. The trans-presented IL-15 is essential to mediate the biological effects on T lymphocytes and NK cells. Here we show that IL-15, but not IL-15Ra, is required for the development of spontaneous and virus-induced T1D, viral clearance and for antigen cross-presentation to CD8 1 T lymphocytes. Our findings provide insight into the complexities of IL-15 signalling in the initiation and maintenance of CD8 1 T cell-mediated immune responses. Cellular & Molecular Immunology

show abstract

Natural, Proteolytic Release of a Soluble Form of Human IL-15 Receptor α-Chain That Behaves as a Specific, High Affinity IL-15 Antagonist

Cited by 123 publications

References 44 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

An Antibody Fusion Protein for Cancer Immunotherapy Mimicking IL-15 trans-Presentation at the Tumor Site

Trans-presentation of interleukin-15 by interleukin-15 receptor alpha is dispensable for the pathogenesis of autoimmune type 1 diabetes

Contact Info

Product

Resources

About