The International Journal of Biochemistry & Cell Biology
Molecules in focusThe roles of interleukin-15 receptor α: Trans-presentation, receptor component, or both?
Introduction
Interleukin 15 receptor α (IL-15Rα) was discovered as a high affinity IL-15 binding protein (Ka = 1011) that was believed to form a heterotrimeric receptor complex with the IL-2/IL-15Rβ and common γ chain (γC) (Anderson et al., 1995, Giri et al., 1995). Since IL-15 binds with moderate affinity to the IL-2/IL-15RβγC (Ka = 109) dimeric complex and signals in the absence of IL-15Rα, it was hypothesized that the IL-15Rα was important for conferring high affinity binding to the trimeric complex (Anderson et al., 1995). In contrast, a novel function for IL-15Rα termed trans-presentation has recently been described and is believed to be unique among cytokine receptors (Dubois, Mariner, Waldmann, & Tagaya, 2002) (Fig. 1). The trans-presentation theory proposes that IL-15Rα presents active IL-15 in trans to opposing cells expressing the βγ complex, thereby transducing a signal. Still, it remains possible that in some situations, IL-15Rα acts with the βγ subunits in the traditional sense. The potential, diverse roles of IL-15Rα will be discussed in this review.
Section snippets
Structure
The human and mouse IL-15Rα genes map to chromosome 10 and chromosome 2, respectively, and the encoded proteins share 54% amino acid homology (Anderson et al., 1995, Giri et al., 1995). Although it is structurally related to IL-2Rα, IL-15Rα is not homologous to IL-2Rα or other known cytokine receptors at the amino acid level. Specific domains of the IL-15Rα protein have been described: signal peptide, sushi domain, hinge, proline–threonine rich region, transmembrane domain and the cytoplasmic
Synthesis and expression
IL-15Rα transcripts are expressed by a wide variety of cell types, including most haematopoetic cells and many parenchymal cells (Giri et al., 1995). Little is known about IL-15Rα protein expression because reagents for detection of IL-15Rα have only recently become available. However, the broad expression pattern of IL-15Rα mRNA by cell types that apparently lack the IL-2/IL-15Rβ and/or γC suggests that IL-15Rα may function in a manner other than as a component of a heterotrimeric receptor
Biological functions
In vivo importance of IL-15Rα and IL-15 was first demonstrated in IL-15Rα−/− and IL-15−/− mice. These mice display a decreased number of total CD8 T cells, and are deficient in memory-phenotype CD8 T cells, NK cells, NK/T cells and some subsets of intestinal intraepithelial lymphocytes (Kennedy et al., 2000, Lodolce et al., 1998). The similar phenotype of IL-15Rα−/− and IL-15−/− mice suggested that the action of IL-15 was likely mediated by a single receptor complex. As these defects were
Medical importance
A number of IL-15 functions could be exploited for medical purposes. The addition of IL-15 at particular times during an immune response may enhance T cell responses or the development of memory to pathogens or tumors. Furthermore, inflammatory diseases such as rheumatoid arthritis are associated with an increase in IL-15 levels, and thus these situations may benefit from blocking the actions of IL-15. Inhibition of IL-15 has been attempted with blocking agents, such as a IL-15Rα and chimeric
Acknowledgments
Work in our laboratory is supported by grants from the National Institutes of Health.
References (17)
- et al.
Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes
J. Biol. Chem.
(1995) - et al.
Natural soluble interleukin-15Ralpha is generated by cleavage that involves the tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17)
J. Biol. Chem.
(2004) - et al.
Natural splicing of exon 2 of human interleukin-15 receptor alpha-chain mRNA results in a shortened form with a distinct pattern of expression
J. Biol. Chem.
(1999) - et al.
IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells
Immunity
(2002) - et al.
IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation
Immunity
(1998) - et al.
Trans-regulation of memory CD8 T cell prolferation by IL-15Rα+ bone marrow-derived cells
Blood
(2004) - et al.
IL-15 promotes the survival of naive and memory phenotype CD8(+) T cells
J. Immunol.
(2003) - et al.
Mast cells express novel functional IL-15 receptor alpha isoforms
J. Immunol.
(2003)