A cytokine was identified that stimulated the proliferation of T lymphocytes, and a complementary DNA clone encoding this new T cell growth factor was isolated. The cytokine, designated interleukin-15 (IL-15), is produced by a wide variety of cells and tissues and shares many biological properties with IL-2. Monoclonal antibodies to the beta chain of the IL-2 receptor inhibited the biological activity of IL-15, and IL-15 competed for binding with IL-2, indicating that IL-15 uses components of the IL-2 receptor.

The tumor necrosis factor (TNF) superfamily of cytokines includes both soluble and membrane-bound proteins that regulate immune responses. A member of the human TNF family, BLyS (B lymphocyte stimulator), was identified that induced B cell proliferation and immunoglobulin secretion. BLyS expression on human monocytes could be up-regulated by interferon-gamma. Soluble BLyS functioned as a potent B cell growth factor in costimulation assays. Administration of soluble recombinant BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum immunoglobulin concentrations. The B cell tropism of BLyS is consistent with its receptor expression on B-lineage cells. The biological profile of BLyS suggests it is involved in monocyte-driven B cell activation.

SummaryInterleukin 15 (IL-15) is a novel cytokine that has recently been doned and expressed. Whereas it has no sequence homology with IL-2, IL-15 interacts with components of the IL-2 receptor (IL-2R). In the present study we performed a functional analysis of recombinant IL-15 on phenotypically and functionally distinct popttlations of highly purified human natural killer (NK) cells. The CD56 b~ht subset of human NK cells constitutively expresses the high affinity IL-2R and exhibits a brisk proliferative response after the binding of picomolar amounts of IL-2. Using a proliferation assay, IL-15 demonstrated a very steep dose-response curve that was distinct from the dose-response curve for IL-2. The proliferative effects of IL-15 could be abrogated by anti-IL-2R~ (p75), but not by anti-IL-2Rc~ (p55). The proliferative effects of IL-2 on CD56bns ht NK cells could be inhibited by both antibodies. CD56 ~n NK cells express the intermediate affinity IL-2R in the absence of the high affinity IL-2R. Activation of CD56 a~ NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytotoxic activity, antibodydependent cdlular cytotoxicity, and NK cell production of interferon % tumor necrosis factor c~, and granulocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cytotoxic activity could be completely blocked by anti-IL-21L8 monoclonal antibody. The binding of radiolabded IL-2 and IL-15 to CD56 d~n NK cells was inhibited in the presence of anti-IL-21LB. Scatchard analysis of radiolabeled IL-15 and IL-2 binding to NK-enriched human lymphocytes revealed the presence of high and intermediate affinity receptors for both ligands. IL-15 is a ligand that activates human NK cells through components of the IL-2R in a pattern that is similar but not identical to that of IL-2. Unlike IL-2, IL-15 is produced by activated monocytes/macrophages. The discovery of IL-15 may increase our understanding of how monocytes/macrophages participate in the regulation of NK cell function.

We have recently cloned a novel cytokine, IL‐15, with shared bioactivities but no sequence homology with IL‐2. We found high affinity IL‐15 binding to many cell types, including cells of non‐lymphoid origin. Analysis of IL‐15 interaction with subunits of the IL‐2 receptor (IL‐2R) revealed that the alpha subunit was not involved in IL‐15 binding. We demonstrated directly in cells transfected with IL‐2R subunits that both the beta and gamma chains are required for IL‐15 binding and signaling. Hence, IL‐15, like IL‐2, IL‐4 and IL‐7, utilizes the common IL‐2R gamma subunit found to be defective in X‐linked severe combined immunodeficiency in humans. IL‐15 is the only cytokine other than IL‐2 that has also been shown to share the beta signaling subunit of IL‐2R. The differential ability of some cells to bind and respond to IL‐2 and IL‐15 implies the existence of an additional IL‐15‐specific component.

Interleukin-1 (IL-1) interacts with cells through two types of binding molecules, IL-1 type I receptor (IL-1R I) and IL-1R II. The function of IL-1R II is unknown. In studies using monoclonal antibodies, IL-1 prolonged the in vitro survival of polymorphonuclear cells (PMN) through IL-1R I, and IL-4 antagonized the action of IL-1 by inducing expression and release of IL-1R II. Dexamethasone also induced expression and release of the IL-1R II in PMN. These results, together with the effect of antibodies to IL-1R on IL-1-induced production of cytokines in monocytes, indicate that IL-1 acts on myelomonocytic cells through IL-1R I and that IL-1R II inhibits IL-1 activity by acting as a decoy target for IL-1. The existence of multiple pathways of regulation emphasizes the need for tight control of IL-1 action.