Interleukin (IL)-15 is a cytokine that acts on a wide range of cell types but is most crucial for the development, homeostasis, and function of a specific group of immune cells that includes CD8 T cells, NK cells, NKT cells, and CD8αα intraepithelial lymphocytes. IL-15 signals are transmitted through the IL-2/15Rβ and common γ (γC) chains; however, it is the delivery of IL-15 to these signaling components that is quite unique. As opposed to other cytokines that are secreted, IL-15 primarily exists bound to the high affinity IL-15Rα. When IL-15/IL-15Rα complexes are shuttled to the cell surface, they can stimulate opposing cells through the β/γC receptor complex. This novel mechanism of IL-15 delivery has been called trans-presentation. This review discusses how the theory of trans-presentation came to be, evidence that it is the major mechanism of action, the current understanding of the cell types thought to mediate trans-presentation, and possible alternatives for IL-15 delivery.

Interleukin-15 (IL-15 IntroductionThe generation and maintenance of memory CD8 T cells is regulated by multiple mechanisms that involve both early programming of memory T-cell precursors as well as a continuous supply of external signals. 1,2 Whereas the events and signals that program memory precursors are not well understood, interleukin-15 (IL-15) has clearly been shown to drive the generation and maintenance of memory CD8 T cells. 3,4 The recent evidence that IL-15 is delivered through the mechanism of transpresentation via IL-15R␣ by cell-cell contact 5 opens up many questions in the field of memory CD8 T-cell homeostasis, the foremost being the identity of the cell transpresenting IL-15 to memory CD8 T cells.To better understand how IL-15 transpresentation is regulated, the identity of the cell type mediating IL-15 transpresentation must be known. Studies attempting to address this have found that either parenchymal or hematopoietic cells mediate transpresentation, depending on the responding lymphocyte. 6,7 This finding is seminal as it shows that cells can be in an IL-15R␣ ϩ environment and remain ignorant to IL-15. Considering that IL-15R␣ is ubiquitously expressed, it is surprising that the responding cell has such strict requirements for a specific cell to transpresent IL-15. 8 In contrast to IL-15R␣ expression, IL-15 protein is not believed to be expressed by many IL-15R␣-expressing cells (ie, T cells); however, expression of IL-15 has been difficult to determine as reagents detecting IL-15 protein have been limited. As such, multiple studies using functional readouts have found that coexpression of IL-15 and IL-15R␣ is integral for a cell to transpresent IL-15. [9][10][11] These observations emphasize that the identity of an IL-15 transpresenting cell may not simply be implied by the expression of IL-15R␣ but rather is better determined through functional analysis.For memory CD8 T cells, in vivo studies found that IL-15R␣-expressing hematopoietic cells are the dominant cell types driving homeostatic proliferation. 7,12 The hematopoietic cells providing the IL-15 signal are RAG-1-independent, indicating that IL-15 transpresentation is not mediated by either T or B lymphocytes. 9 As DCs, monocytes, and macrophages have been shown to express IL-15R␣ protein and are capable of inducing IL-15, 13,14 these cells are potential mediators of IL-15 transpresentation. Indeed, bone marrow (BM)-derived DCs and some monocytic cell lines can transpresent IL-15 in vitro 5 ; however, whether their analogous in vivo counterparts transpresent IL-15 to CD8 T cells is not known. Since IL-15 transpresentation requires cell-cell interactions and DCs have a natural propensity for T-cell interactions, DCs are a prime candidate to transpresent IL-15 to memory CD8 T cells. Therefore, the goal of this study was to examine the contribution of DCs in transpresentation of IL-15 to CD8 T cells.In this study, we demonstrate that DCs transpresent IL-15 to CD8 T cells driving specific functions during differentiation. Although IL-15 ...

IL-15 is a key component that regulates the development and homeostasis of NK cells and is delivered through a mechanism termed trans-presentation. During development, multiple events must proceed to generate a functional mature population of NK cells that are vital for tumor and viral immunity. Nevertheless, how IL-15 regulates these various events and more importantly what cells provide IL-15 to NK cells to drive these events is unclear. It is known dendritic cells (DC) can activate NK cells via IL-15 trans-presentation; however, the ability of DC to use IL-15 trans-presentation to promote the development and homeostatic maintenance of NK cell has not been established. In this current study, we show that IL-15 trans-presentation solely by CD11c+ cells assists the in vivo development and maintenance of NK cells. More specifically, DC-mediated IL-15 trans-presentation drove the differentiation of NK cells, which included the up-regulation of the activating and inhibitory Ly49 receptors. Although these cells did not harbor a mature CD11bhigh phenotype, they were capable of degranulating and producing IFN-γ upon stimulation similar to wild-type NK cells. In addition, DC facilitated the survival of mature NK cells via IL-15 trans-presentation in the periphery. Thus, an additional role for NK-DC interactions has been identified whereby DC support the developmental and homeostatic niche of NK cells.

Type I IFNs, including IFN-α, enhance Ag presentation and promote the expansion, survival, and effector function of CD8+ CTL during viral infection. Because these are ideal characteristics for a vaccine adjuvant, we examined the efficacy and mechanism of exogenous IFN-α as an adjuvant for antimelanoma peptide vaccination. We studied the expansion of pmel-1 transgenic CD8+ T cells specific for the gp100 melanocyte differentiation Ag after vaccination of mice with gp10025–33 peptide in IFA. IFN-α synergized with peptide vaccination in a dose-dependent manner by boosting relative and absolute numbers of gp100-specific T cells that suppressed B16 melanoma growth. IFN-α dramatically increased the accumulation of gp100-specific, IFN-γ-secreting, CD8+ T cells in the tumor through reduced apoptosis and enhanced proliferation of Ag-specific CD8+ T cells. IFN-α treatment also greatly increased the long-term maintenance of pmel-1 CD8+ T cells with an effector memory phenotype, a process that required expression of IFN-α receptor on the T cells and IL-15 in the host. These results demonstrate the efficacy of IFN-α as an adjuvant for peptide vaccination, give insight into its mechanism of action, and provide a rationale for clinical trials in which vaccination is combined with standard-of-care IFN-α therapy for melanoma.

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