We report intriguing aspects of the contribution of IL-15Ralpha to IL-15 functions. Consistent with high-affinity interactions between IL-15 and IL-15Ralpha, these two molecules form stable complexes on the cell surface of activated monocytes. The formation of IL-15/IL-15Ralpha complexes on cell surfaces induces a trans-endosomal recycling of IL-15 leading to the persistence of surface-bound IL-15 due to the constant reappearance of IL-15 on plasma membranes. This complex contributes to the long survival of T cells expressing IL-15Ralpha after IL-15 withdrawal. Finally, these complexes on activated monocytes present IL-15 in trans to target cells such as CD8(+) T cells that express only IL-2/15Rbeta and gammac upon cell-cell interaction.

Interleukin-15 (IL-15) is a 14-to 15-kDa member of the 4 α-helix bundle family of cytokines. IL-15 expression is controlled at the levels of transcription, translation, and intracellular trafficking. In particular, IL-15 protein is posttranscriptionally regulated by multiple controlling elements that impede translation, including 12 upstream AUGs of the 5 UTR, 2 unusual signal peptides, and the C-terminus of the mature protein. IL-15 uses two distinct receptor and signaling pathways. In T and NK cells the IL-15 receptor includes IL-2/15Rβ and γ c subunits, which are shared with IL-2, and an IL-15-specific receptor subunit, IL-15Rα. Mast cells respond to IL-15 with a receptor system that does not share elements with the IL-2 receptor but uses a novel 60-to 65-kDa IL-15RX subunit. In mast cells IL-15 signaling involves Jak2/STAT5 activation rather than the Jak1/Jak3 and

IL-15 and IL-2 possess similar properties, including the ability to induce T cell proliferation. However, whereas IL-2 can promote apoptosis and limit CD8 ؉ memory T cell survival and proliferation, IL-15 helps maintain a memory CD8 ؉ T cell population and can inhibit apoptosis. We sought to determine whether IL-15 could enhance the in vivo function of tumor͞self-reactive CD8 ؉ T cells by using a T cell receptor transgenic mouse (pmel-1) whose CD8 ؉ T cells recognize an epitope derived from the self͞melanoma antigen gp100. By removing endogenous IL-15 by using tumor-bearing IL-15 knockout hosts or supplementing IL-15 by means of exogenous administration, as a component of culture media or as a transgene expressed by adoptively transferred T cells, we demonstrate that IL-15 can improve the in vivo antitumor activity of adoptively transferred CD8 ؉ T cells. These results provide several avenues for improving adoptive immunotherapy of cancer in patients.

whereas there is no IL-15 mRNA demonstrable in normal Metabolism Branch, National Cancer Institute resting or activated T cells as assessed by Northern blot National Institutes of Health analysis. Nevertheless, there is widespread expression Bethesda, Maryland 20892 of IL-15 message, which appears most abundantly in placenta and skeletal muscle but also in kidney, lung, and heart as well as lipopolysaccharide (LPS)-activated Intercellular communications essential for regulatory monocytes Bamford et al., 1996). and effector actions involved in immune responses areThe expression of the cytokine IL-2 is controlled preoften mediated by a series of proteins termed cytokines.dominantly at the level of transcription and message Cytokines exhibit a high degree of redundancy and stabilization. In contrast, the synthesis and secretion of pleiotropy, controlling a wide range of functions in vari-IL-15 appears to be controlled at multiple levels (e.g., ous cell types. The redundancy is explained in part by translation, and entry into secretory pathway) in addition the promiscuity of receptors; that is, by the sharing of to transcription (Bamford et al., 1996). An additional difcommon receptor subunits among members of the cytoference between IL-15 and IL-2 is that IL-15 uses a kine receptor family (Bazan, 1990;Sato and Miyajima, distinct receptor and signaling system in select cells. In 1994; Kishimoto et al., 1994). Each cytokine has its own particular, IL-15 stimulates the proliferation of mast cells private receptor but may also share a public receptor that do not respond to IL-2 (Tagaya et al., 1996). In with other cytokines. For example, receptors for insuch cells, IL-15 binding and signaling involves a novel terleukin-6 (IL-6), leukemia inhibitory factor, oncostatin receptor system that does not share any subunits with M, ciliary neurotropic factor, IL-11, and cardiotropin-1 the IL-2R system. Furthermore, this novel IL-15R system share a gp130 signaling unit, whereas IL-3, IL-5, and utilizes a signal transduction pathway distinct from the granulocyte/macrophage colony-stimulating factor utione used by the IL-2/IL-15R system in T cells. lize a common ␤c receptor subunit (Sato and Miyajima 1994, Kishimoto et al. 1994). There is a similar sharing Discovery of IL-15 of receptor elements within the IL-2 receptor (IL-2R) IL-15 was discovered because of the capacity of culture system, a system that involves ␣, ␤, and ␥ subunits supernatants from two cell lines, CV-1/EBNA and the (Noguchi et al., 1993a;Kondo et al., 1993). This sharing HTLV-1-associated HuT-102, to stimulate proliferation of IL-2R subunits was anticipated by the initially paraof the cytokine-dependent murine T cell line CTLL-2 doxical observations that the immune system of mice (Burton et al., 1994;Bamford et al., 1994; Grabstein et made deficient in IL-2 by homologous recombination al., 1994). The HTLV-1-associated HuT-102 adult T cell developed relatively normally during the first few weeks leukemia cell line was shown to secrete a 14-15 kDa of life, wherea...

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Natural killer (NK) cells are critical for both innate and adaptive immunity. The development of NK cells requires interactions between their progenitors and the bone-marrow microenvironment; however, little is known about the molecular nature of such interactions. Mice that do not express the transcription factor interferon-regulatory factor-1 (IRF-1; such mice are IRF-1(-/-) mice) have been shown to exhibit a severe NK-cell deficiency. Here we demonstrate that the lack of IRF-1 affects the radiation-resistant cells that constitute the microenvironment required for NK-cell development, but not the NK-cell progenitors themselves. We also show that IRF-1(-/-) bone-marrow cells can generate functional NK cells when cultured with the cytokine interleukin-15 and that the interleukin-15 gene is transcriptionally regulated by IRF-1. These results reveal, for the first time, a molecular mechanism by which the bone-marrow microenvironment supports NK-cell development.

HTLV‐I transformed T cells not only express a large number of interleukin‐2 receptors [IL‐2R/p55(Tac)], but also produce a factor named ATL‐derived factor (ADF) that augments the expression of IL‐2R/p55(Tac). Based on a partial N‐terminal amino acid sequence, complementary DNA (cDNA) clones for human and mouse ADF were isolated and sequenced. Recombinant ADF produced by COS‐7 monkey kidney cells showed IL‐2R/Tac inducing activity on YT cells, which are sensitive for ADF. ADF mRNA was strongly expressed in HTLV‐I(+) T cells lines, but not in inactivated cells (THP‐1, unstimulated PBMC). Furthermore, in normal human peripheral blood mononuclear cells, the expression of ADF mRNA was enhanced by mitogens or phorbol myristate acetate, suggesting a possible involvement of ADF in the lymphocyte activation. Homology analysis revealed an unexpected relationship between ADF and dithiol‐reducing enzyme, thioredoxin, involved in many important biological reactions such as the conversion of ribonucleotides into deoxyribonucleotides, or the stabilization of glucocorticoid receptors. The biological significance of the generation of a redox potential in lymphocyte activation, and the possible involvement of dithiol reduction in the induction of IL‐2R/Tac are discussed.