How a Cytokine Is Chaperoned through the Secretory Pathway by Complexing with Its Own Receptor: Lessons from Interleukin-15 (IL-15)/IL-15 Receptor α

Duitman, Erwin H.; Orinska, Zane; Bulanova, Elena; Paus, Ralf; Bulfone–Paus∥, Silvia

doi:10.1128/mcb.00375-10

Cited by 15 publications

(26 citation statements)

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“…Mixing experiments providing additional purified sIL-15R␣ suggested that the single-chain IL-15 is not present in detectable amounts in serum, reinforcing the conclusion that IL-15R␣ serves as a chaperone molecule rescuing unstable single-chain IL-15 from intracellular degradation and promoting its secretion. 21,22,33,34 In agreement with the human data, similar analysis performed in normal, lymphodepleted, or IL-15R␣ knockout mice revealed that all detectable IL-15 in mouse serum is bound to sIL-15R␣. The absence of single-chain IL-15 both under physiologic conditions or on lymphopenia induction in mice suggests that lymphodepleting treatments only affect the level but not the form of IL-15 produced in the body (ie, IL-15/IL-15R␣ complexes).…”

Section: Discussionsupporting

confidence: 69%

Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum

Bergamaschi¹,

Bear

Rosati³

et al. 2012

Blood

146

151

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IntroductionIL-15 is a member of the common ␥-chain family of cytokines and was initially characterized as a T-cell proliferation factor. 1,2 IL-15 is a growth, mobilization, and activation factor for important lymphocyte populations, including NK, CD8, and intraepithelial lymphocytes. 3-6 IL-15 and IL-2 share the same IL-2/IL-15␤␥ receptor (IL-2/IL-15R␤␥), 7 but their biologic effects at the level of organism are different, as shown by studies in knockout mice. The lack of IL-15 in vivo results in severe defects in the development and function of the immune system. 8,9 Although lymphocytes from IL-2 knockout mice fail to proliferate in response to polyclonal T-cell mitogens in vitro, 10 the common features developing in these mice are lymphocyte activation and autoimmunity. 11 In humans, IL-2-receptor ␣ (IL-2R␣) deficiency has been linked to a paradoxical combination of immunodeficiency and autoimmunity in 2 patients. 12,13 The biologic differences of IL-2 and IL-15 are determined by their different production sites, 5,14 their strength of association with the membrane proteins IL-2R␣ and IL-15R␣, 15 respectively, and the regulation of these receptor molecules. IL-2 is produced by activated lymphocytes, whereas IL-15 is produced by stromal cells of several tissues, and by antigen-presenting cells. IL-15R␣ has a high affinity for IL-15 (K d ϳ 10 Ϫ11 M). 15 In contrast, IL-2R␣ has lower affinity for IL-2 (K d ϳ 10 Ϫ8 M) and is expressed mainly on activated T cells and persistently on Treg.IL-15 is known to act on the surface of the cell in complex with IL-15R␣ to engage the IL-2/IL-15R␤␥ complex in nearby cells, a process termed trans-presentation. 16 Genetic and cell transfer experiments have shown that IL-15 and IL-15R␣ need to reside in the same cell for appropriate function. [17][18][19][20] We previously demonstrated that coexpression of the 2 molecules in the same cell leads to rapid intracellular association of IL-15 and IL-15R␣ in the endoplasmic reticulum, stabilization of both molecules, and the generation of a stable complex that can translocate to the cell membrane, where it is bioactive. 21,22 In addition, the surface heterodimer is rapidly cleaved and released in the plasma as bioactive cytokine. 22 Our experiments using IL-15 complexed to a C-terminal deletion of IL-15R␣ containing only the soluble extracellular fragment demonstrated that this complex is bioactive in vivo in the absence of any membrane-bound form of IL-15. 22 These results explain the necessity for the coordinate expression of IL-15 and IL-15R␣ in the same cell for physiologic function, [17][18][19] and predict that the circulating form of IL-15 in biologic fluids is in complex with soluble IL-15R␣ (sIL-15R␣).Although these results suggested that the main bioactive form of IL-15 is in a complex with IL-15R␣, 21-26 the actual form of IL-15 produced in humans has not been identified. The levels of IL-15 in normal human serum are close to the limit of detection of the existing assay (ϳ 1 pg/mL). Therefore, we studied the nature of the...

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Section: Discussionsupporting

confidence: 69%

Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum

Bergamaschi¹,

Bear

Rosati³

et al. 2012

Blood

146

151

View full text Add to dashboard Cite

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“…However, IL-15 is known to be essentially trans-presented as a bioactive IL-15/IL15Ra complex by producing cells to neighboring cells bearing the IL-2/IL-15Rb and the g c chains. 22,23 In agreement, the protective effect of monocytes on B cells was significantly reinforced in the presence of exogeneous IL-15, suggesting that resting B cells could directly respond to IL-15-presenting cells.…”

Section: Monocytes/macrophages Efficiently Trans-present Il-15 To B Csupporting

confidence: 63%

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

et al. 2011

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Interleukin-15 (IL-15) has been extensively studied for its role in the survival and proliferation of NK and T cells through a unique mechanism of trans-presentation by producer cells. Conversely, whereas activated B cells have been described as IL-15-responding cells, the cellular and molecular context sustaining this effect remains unexplored. In this study, we found that, whereas human B cells could not respond to soluble IL-15, monocytes and lymphoid tissue-derived macrophages but not stromal cells efficiently trans-present IL-15 to normal B cells and cooperate with T-cell-derived CD40L to promote IL-15-dependent B-cell proliferation. Furthermore, CD40L signaling triggers a Src-independent upregulation of STAT5 expression and favors a Src-dependent phosphorylation of STAT5 in response to IL-15. In follicular lymphoma (FL), immunohistochemical studies reported a strong relationship between malignant B cells, infiltrating macrophages and T cells. We show here an overexpression of IL-15 in purified tumor-associated macrophages, and STAT5A in purified tumor B cells. Moreover, FL B cells respond to IL-15 trans-presented by monocytes/macrophages, in particular, in the presence of CD40L-mediated signaling. This cooperation between IL-15 and CD40L reinforces the importance of tumor microenvironment and unravels a mechanism of FL growth that should be considered if using IL-15 as a drug in this disease.

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“…IL-15 is released only when bound to its private a-chain receptor, leaving other unbound forms behind. 12 Thus, our data cannot exclude the possibility that the increased number of monocytes of LTNP and healthy controls , and healthy controls (n = 12) were stimulated overnight (IFN) or not (NS) with IFN-c, and the concentrations of IL-15 were assessed in the collected supernatants. The data were analyzed using a paired t test, and there were significant differences after IFNc stimulation in all of the groups but not between them: ***p < 0.001; **p < 0.005.…”

Section: Discussionmentioning

confidence: 99%

“…10,12 Such close control of the production of IL-15 by the a-chain of the IL-15 receptor 10,42 implies the coordinated expression of both genes and explains very limited extracellular release of this cytokine. Any disregulation of this control may therefore lead to the excessive release and overexpression of IL-15, and thus contribute to the development of autoimmune or inflammatory diseases.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 The IL-15Ra chain not only acts as a classical chaperone to the cell membrane, but it also helps regulate the expression of IL-15 by binding it within the intracellular compartment and transporting it through the Golgi apparatus. 12 Because of its high affinity binding to IL-15Ra and cell recycling, IL-15 is hardly detectable in soluble form even after cell stimulation. It is expressed by monocytes, macrophages, dendritic cells, and a number of nonhematopoietic cells, and the expression of the IL-15 gene is increased after interferon IFN-c, 9 lipopolysaccharide (LPS), 13 or viral stimulation 14 in human monocytes.…”

Section: T He Main Immunological Effect Of Hiv-1 Infection Is the Promentioning

confidence: 99%

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Expression of Interleukin-15 and Interleukin-15Rα in Monocytes of HIV Type 1-Infected Patients with Different Courses of Disease Progression

Tarkowski

Ferraris²,

Martone³

et al. 2012

AIDS Research and Human Retroviruses

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Interleukin-15 (IL-15) enhances the effector mechanisms of anti-HIV immune responses and thus is considered a potential adjuvant of HIV-1 vaccine. However, there are a lack of data concerning the relationships between IL-15 expression and regulation in HIV-1-infected patients and the course of disease progression. We found that IL-15, but not IL-15Ra, is expressed at significantly higher levels in the CD14 + monocytes [stimulated or not with interferon (IFN)-c] of long-term nonprogressors (LTNP) than in those of HIV-1 progressors or healthy controls. There was no between-group difference in the amounts of soluble IL-15 released from the cells. We also found that like the healthy controls, the LTNP expressed the IL-15 and IL-15Ra genes in a more coordinated manner than the progressors. Our findings show that there are significant differences in IL-15 expression between patients with different courses of HIV infection, and that the coordinated expression of the IL-15 and IL-15Ra genes is dysregulated in patients with progressive disease. They also provide important information concerning the mechanisms of infection and the potential use of IL-15 as a therapeutic agent.

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How a Cytokine Is Chaperoned through the Secretory Pathway by Complexing with Its Own Receptor: Lessons from Interleukin-15 (IL-15)/IL-15 Receptor α

Cited by 15 publications

References 0 publications

Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum

Circulating IL-15 exists as heterodimeric complex with soluble IL-15Rα in human and mouse serum

Monocytes and T cells cooperate to favor normal and follicular lymphoma B-cell growth: role of IL-15 and CD40L signaling

Expression of Interleukin-15 and Interleukin-15Rα in Monocytes of HIV Type 1-Infected Patients with Different Courses of Disease Progression

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