SurveyIL-15/IL-15 receptor biology: A guided tour through an expanding universe
Introduction
Interleukin-15 (IL-15) is a pleiotropic cytokine of the 4-α-helix bundle cytokine family that includes not only cytokines such as IL-2, IL-3, IL-4, IL-6 and IL-21, but also growth factors like granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), erythropoietin and classical hormones, including human growth hormone and prolactin [1]. As a member of this large and very diverse family, IL-15 exerts profound effects on the proliferation, survival and differentiation of many more distinct cell types than was originally appreciated at the time of its discovery.
IL-15 was independently discovered in 1994 by two groups, due to its ability to mimic IL-2-dependent T cell proliferation [2], [3]. Burton et al. demonstrated that the human T-cell leukemia virus-1 (HTLV-1) cell line HuT-102 secreted a 14 kDa lymphokine capable of stimulating T cell proliferation and large granular lymphocytes activation, which was provisionally designated as IL-T [2]. Simultaneously, Grabstein et al. reported the isolation of a 14–15 kDa cytokine termed IL-15, which shared many biological properties with IL-2, from the supernatants of the simian kidney epithelial cell line CV-1/EBNA [3]. Human IL-15 has been cloned from the human bone marrow (BM) stromal cell line IMTLH, using simian IL-15 cDNA as a probe [3]. The predominant IL-15 message in HuT-102 cells corresponded to a chimeric mRNA where a segment of the long terminal repeat of HTLV-1 was fused in frame upstream of the 5′-untranslated region (UTR) of IL-15, thereby eliminating about 200 nucleotides of the IL-15 5′-UTR, including 8 of 10 AUGs, which are present in normal IL-15 messages and impede IL-15 translation [4]. Later, it was confirmed using anti-cytokine antibodies that both groups had identified the same interleukin [4]. This was designated IL-15.
A special feature of IL-15 is that it shares with IL-2, another member of the 4-α-helix bundle cytokine family, the IL-2 receptor beta (IL-2Rβ) and IL-2 receptor gamma/gamma common (IL-2Rγ/γc) chains [5]. The γc receptor chain is also shared by several other cytokines, such as IL-4, IL-7, IL-9 and IL-21, all of which use additional private receptor subunit(s) responsible for the specificity of binding and/or downstream signaling [6]. Given that cytokines often share receptor subunits and can therefore display a high degree of redundancy, the existing similarities in the action between IL-2 and IL-15 on cells of the same type are not surprising [2], [3], [7]. Together with the observed proliferation-stimulatory effects of both cytokines on various T-cell populations in vitro, this had initially encouraged the speculation that IL-2 and IL-15 exert very similar, if not identical functions [2], [3]. However, a series of later studies have shown that, despite their many overlapping functional properties, IL-2 and IL-15 are, in fact, quite distinct players in the immune system (see below).
In essence, the concept has emerged that while IL-2 operates as a key modulator of T-cell-dependent adaptive immune responses, IL-15 serves a much broader spectrum of bioregulatory purposes. These range from those of a prototypic cytokine of innate immunity [8] via the modulation of selected adaptive immune responses [9], [10] and a key role in the development of distinct immunocyte populations (namely natural killer (NK) cells) [11] to those of a potent, general inhibitor of apoptosis in multiple systems [12]. In addition, while IL-2 expression appears to be restricted to T cells [13], and possibly dendritic cells (DCs) stimulated with LPS [14], numerous different cell types engage in IL-15 transcription (even though much fewer seem to actually translate and secrete it (see below)). As the literature witnesses a steady flow of documented or proposed new functions of IL-15, initial proposals that IL-15 is a rather special member of the 4-α-helix bundle family with distinct functions have turned into an irreversible torrent of evidence [11], [12], [15], [16], [17].
This review argues that IL-15, indeed, is not only an unusually pleiotropic, but also a unique cytokine in several respects (including mechanisms of cytokine synthesis, presentation, secretion and cytokine-induced signaling events), which we shall explore. Undoubtedly, one reason for the distinctness of IL-2 and IL-15 functions is that each cytokine has its own unique high affinity α chain, which recognizes only its cognate cytokine, thereby conferring ligand specificity [18], [19]. However, as we shall emphasize, the differences between IL-2 and IL-15 (and, for that matter, any other member of this cytokine family!) do not stop here, but extend to almost every level of cytokine biology—from the regulation of cytokine gene transcription, translation, cytokine membrane expression and secretion, and the signaling induced by it. This ever-expanding universe of IL-15/IL-15R biology makes it one of the currently most fascinating in the cytokine world. Since the functional importance of IL-15/IL-15R biology in T cells and NK cells has been exceptionally well-covered before [8], [9], [10], [11], [17], the current review will purposely explore the physiological role of IL-15/IL-15R signaling in systems other than T and NK cells.
Section snippets
Genetic and structural features of IL-15
IL-15 is conserved among different species, exhibiting 97% sequence identity in the coding region between human and simian IL-15 [3], 82% identity between human and porcine IL-15 [20] and 73% of identity comparing human and mouse forms of this cytokine [21]. Recently, rabbit [22], feline [23], woodchuck [24] and chicken [25] IL-15 have been cloned, as well. The IL-15 gene spans more than 34 kb, and was mapped to the human chromosome 4q31 and the central region of the mouse chromosome 8 [21], [26]
High affinity IL-15 receptor α
IL-15 receptor α (IL-15Rα) is a type I transmembrane protein structurally related to the IL-2Rα chain [18], [19] (Fig. 2). In both the human and the mouse genome, the IL-15Rα and IL-2Rα genes are very closely linked, mapped to chromosome 10 in human and to chromosome 2 in mouse, and have similarities in the intron–exon structure [19]. This suggests that these genes have a common ancestral origin, and positions these two receptors as founding members of a new receptor family [18], [19]. However,
Signaling mediated by the IL-15 receptor
Sharing of receptor subunits (IL-2R/IL-15Rβγ/γc chains) can explain in part the existing functional similarities between IL-2 and IL-15 [5], [64]. IL-15-mediated signaling in T lymphocytes results in the activation of Janus kinase (JAK) [72]. JAKs play critical signaling roles for a number of members of the cytokine receptor superfamily by activating signal transducer and activator of transcription (STAT) proteins [73]. After receptor–ligand interaction, associated JAKs are brought into close
IL-15 and immune cells (except T and NK cells)
It is now recognized that signaling via the IL-15/IL-15R system modulates not only T-cell functions, but numerous different other cell populations, as well. Given that a number of recent reviews have discussed in depth the functional importance of IL-15/IL-15R biology for T lymphocyte development and homeostasis, and memory CD8+ T-cell and NK cell development, maintenance, expansion and activities (see [8], [9], [10], [11], [17]), in the following we shall only explore the functional role of
Clinical relevance
That signaling through the IL-15/IL-15R system is of profound clinical importance has become amply clear in RA, where IL-15 antibodies have already been tested in Phase I/II trials (reviewed in [161]). However, there are several other important clinical fields where IL-15/IL-15R signaling has recently become a focus of interest, and has been explored as a potential target for therapeutic intervention. For example, a number of other autoimmune diseases such as inflammatory bowel disease (IBD),
Conclusions and therapeutic perspectives
IL-15 is a pleiotropic cytokine which regulates the proliferation, survival, secretory activities and differentiation of many more distinct cell types than originally postulated at the time of its identification. IL-15 is a very broadly expressed bioregulator which serves not only as prototypic cytokine of innate immunity but modulates as well selected adaptive immune responses and, in fact, links both. Largely because of its unusually potent anti-apoptotic properties, IL-15 controls the
Acknowledgments
We acknowledge support from the German Research Society (SFB415/A10 to SBP). We apologize to colleagues whose work has not been or might have been cited only indirectly through reviews, owing to space constraints.
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