Comment on Blaser et al, page 2463

Recent studies suggest that the effects of IL-15 are enhanced when IL-15–secreting cells also express the IL-15Rα receptor subunit. Trans-presentation of IL-15 promotes localized immunologic functions that are distinct from IL-2.

Interleukin-2 (IL-2) and IL-15 are distinct cytokines encoded by 2 genes on chromosome 4 (regions q26-q27 and q31, respectively). However, these cytokines share components of a common cell membrane receptor complex, IL-2Rβ (CD122) and IL-2Rγ (CD132), and activation of IL-2Rβγ by either cytokine leads to phosphorylation of the same downstream signaling molecules, primarily within the JAK-STAT pathway. Because IL-2 and IL-15 share this common receptor, many of the immunologic effects of IL-2 and IL-15 are identical. Nevertheless, these 2 cytokines also have clearly distinct biologic functions in vivo.

What, then, distinguishes the biologic effects of IL-2 and IL-15 in vivo? In part, the distinct features of each cytokine reflect the presence of unique receptor components, IL-2Rα (CD25) and IL-15Rα. The genes for IL-2Rα and IL-15Rα are located next to each other on chromosome 10 (p15-14), but the cellular expression of each receptor is independently regulated in different cell types. These unique receptors do not directly mediate signal transduction. However, when combined with IL-2Rβγ, unique trimeric receptor complexes mediate high-affinity binding that is specific for each cytokine. Since the trimeric receptor complex binds ligands with higher affinity than the shared dimeric receptor complex, trimeric complexes are capable of mediating specific responses in the presence of relatively low concentrations of their respective ligands. However, as local concentrations of each cytokine increase, potentially beyond normal physiologic levels, dimeric receptor complexes become engaged and the distinct functions of each cytokine are lost.

Recently, several laboratories have identified an additional novel mechanism that serves to distinguish the functional effects of IL-15 from IL-2.1,2  These studies found that the biologic activity of IL-15 is markedly enhanced when IL-15 is secreted by the same cells that express IL-15Rα. IL-2 does not exhibit similar activity, suggesting that “trans-presentation” of IL-15 is a mechanism to enhance the immunologic effects of this cytokine in a local environment. In contrast, IL-2 appears to be designed to mediate both local and distant effects.

What are the potential immunologic consequences of this unique mechanism of action for IL-15? In this issue of Blood, Blaser and colleagues demonstrate that trans-presentation of IL-15 can lead to significant tissue destruction, namely lethal acute graft-versus-host disease (GVHD), after major histocompatibility complex (MHC)–mismatched hematopoietic stem cell transplantation in a murine model system. In a series of well-controlled experiments, secretion of IL-15 by donor bone marrow cells that also express IL-15Rα was found to contribute to the lethality of GVHD. Transplantation of donor bone marrow that lacked either endogenous IL-15 or IL-15Rα significantly delayed the onset of GVHD. These local effects did not delay systemic reconstitution of donor T cells or graft-versus-tumor effects. Having demonstrated the potential significance of the local effects of IL-15 in this model system, further studies can begin to explore methods to inhibit these local effects in patients with GVHD. Alternatively, it may also be possible to extend the immunologic effects of this cytokine in vivo through the use of synthetic constructs that link IL-15 with specific IL-15Rα domains to produce potent systemic agonists.3,4  In both situations, immunologic interventions can now be based on a better understanding of the complex interactions that occur between these secreted ligands and their multimeric receptors. ▪

1
Burkett PR, Koka R, Chien M, Chai S, Boone DL, Ma A. Coordinate expression and trans presentation of interleukin (IL)-15Ra and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis.
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2
Sandau MM, Schluns KS, Lefrancois L, Jameson SC. Cutting edge: transpresentation of IL-15 by bone marrow-derived cells necessitates expression of IL-15 and IL-15Ra by the same cells.
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2004
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3
Mortier E, Quemener A, Vusio P, et al. Soluble interleukin-15 receptor alpha (IL-15R alpha)-sushi as a selective and potent agonist of IL-15 action through IL-15Rbeta/gamma: hyperagonist IL-15 × IL-15Ra fusion proteins.
J Biol Chem
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2006
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281
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4
Rubinstein MP, Kovar M, Purton JF, et al. Converting IL-15 to a superagonist by binding to soluble IL-15Rα.
Proc Natl Acad Sci U S A
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2006
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103
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9166
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