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.

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-15 (IL-15) is a novel cytokine of the fourhelix bundle family which shares many biological activities with IL-2, probably due to its interaction with the IL-2 receptor 3 and y (IL-2RO and ye) chains.We report here the characterization and molecular cloning of a distinct murine IL-15Ra chain. IL-15Ra alone displays an affinity of binding for IL-15 equivalent to that of the heterotrimeric IL-2R for IL-2. A biologically functional heteromeric IL-15 receptor complex capable of mediating IL-15 responses was generated through reconstruction experiments in a murine myeloid cell line. IL-l5Rca is structurally similar to IL-2Ra; together they define a new cytokine receptor family. The distribution of IL-15 and IL15Ra mRNA suggests that IL-15 may have biological activities distinct from IL-2.

The effects of interferon-γ (IFN-γ) on tight junctions in T84 human intestinal epithelial cells were investigated. Treatment of T84 cells with IFN-γ caused a dose- and time-dependent increase in monolayer permeability as assessed by transepithelial electrical resistance measurements. Examination of specific proteins associated with tight junctions by immunoblotting and confocal microscopy revealed changes in the expression levels and localization of some of these proteins after exposure of the cells to IFN-γ. Specifically, IFN-γ treatment resulted in an almost total loss of zonula occludens (ZO)-1, whereas the levels of ZO-2 and occludin showed relatively modest decreases compared with untreated cells. Loss of ZO-1 was associated with the altered localization of ZO-2 and occludin. In IFN-γ-treated cells, ZO-2 and occludin were diffusely distributed, whereas, in control cells, they, along with ZO-1, were predominantly localized to the tight junctions. Analysis of ZO-1 protein and RNA by pulse chase and RT-PCR, respectively, showed an increase in protein turnover, a decrease in protein synthesis, and a reduction in RNA levels following IFN-γ treatment. In contrast to ZO-1, ZO-2 and occludin did not show any major changes in these parameters. In addition, the organization of actin in the apical and tight junction regions, but not in the mid- or basal regions, of the cells was also perturbed by IFN-γ treatment of cells. Time-course analysis of IFN-γ-induced alterations in ZO-1 expression and apical actin perturbation indicated that these two effects were intimately linked and could not be dissociated. These results suggest that IFN-γ affects barrier function in T84 cells by decreasing the levels of ZO-1 and perturbing apical actin organization, which leads to a disorganization of the tight junction and an increase in paracellular permeability.