Molecules in focus
The roles of interleukin-15 receptor α: Trans-presentation, receptor component, or both?

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Abstract

Interleukin-15 receptor α (IL-15Rα) is a high affinity IL-15 binding protein that is crucial for mediating IL-15 functions such as memory CD8 T cell proliferation and NK, NK/T cell, and intestinal intraepithelial lymphocyte development. However, the mechanism by which IL-15Rα mediates IL-15 functions is unique among cytokines. Originally, IL-15Rα was thought to be a component of a heterotrimeric receptor complex containing the IL-2/IL-15Rβ and common γ chains (γC) that were required for mediating signaling. Although IL-15Rα may in some cases act as a component of this receptor complex, more recent evidence indicates that IL-15Rα predominately functions by presenting IL-15 to opposing cells expressing the IL-15Rβγ signaling components. This theory is consistent with the broad, non-lymphoid expression pattern of IL-15Rα and the evidence that IL-15Rα expression by lymphocytes is dispensable for IL-15 action in vivo. This new concept of cytokine delivery will allow us to better understand the regulation and function IL-15.

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.

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