SummaryThe human cytokine interferon-inducible protein 10 (IP-10) is a small glycoprotein secreted by activated T cells, monocytes, endothelial cells, and keratinocytes, and is structurally related to a family of chemotactic cytokines called chemokines. Although this protein is present in sites of delayed-type hypersensitivity reactions and lepromatous leprosy lesions, the biological activity of IP-10 remains unknown. We report here that recombinant human IP-10 stimulated significant in vitro chemotaxis of human peripheral blood monocytes but not neutrophils. Recombinant human IP-10 also stimulated chemotaxis of stimulated, but not unstimulated, human peripheral blood T lymphocytes. Phenotypic analysis of the stimulated T cell population responsive to IP-10 demonstrated that stimulated CD4 + and CD29 + T cells migrated in response to IP-10. This resembles the biological activity of the previously described T cell chemoattractant R.ANTES. Using an endothelial cell adhesion assay, we demonstrated that stimulated T cells pretreated with optimal doses of IP-10 exhibited a greatly enhanced ability to bind to an interleukin 1-treated endothelial cell monolayer. These results demonstrate that the IP-10 gene encodes for an inflammatory mediator that specifically stimulates the directional migration of T cells and monocytes as well as potentiates T cell adhesion to endothelium.

Interleukin-2 is an autocrine growth factor for T cells which also activates other cells including B cells and natural killer cells. The subunits of the interleukin-2 receptor (IL-2R) lack intrinsic enzymatic activity, but protein tyrosine phosphorylation is a critical event following ligand binding and src family kinases, such as Lck, are known to be activated by IL-2 (refs 5-9). However, IL-2 signalling can occur in the absence of receptor interaction with Lck, suggesting that other protein tyrosine kinases might be important. Here we report that a new member of the Janus family of kinases (Jak-3) is coupled to the IL-2R in human peripheral blood T cells and natural killer cells.

The cytokines interleukin 2 (IL-2) and IL-15 have similar biological effects on T cells and bind common hematopoietin receptor subunits. Pathways that involve Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) have been shown to be important for hematopoietin receptor signaling. In this study we identify the STAT proteins activated by in human T cells. IL-2 and IL-15 rapidly induced the tyrosine phosphorylation of STAT3 and STAT5, and DNA-binding complexes containing STAT3 and STAT5 were rapidly activated by these cytokines in T cells. IL-4 induced tyrosine phosphorylation and activation of STAT3 but not STAT5. JAK1 and JAK3 were tyrosinephosphorylated in response to IL-2 and IL-S15. Hence, the JAK and STAT molecules that are activated in response to IL-2 and IL-15 are similar but differ from those induced by IL-4. These observations identify the STAT proteins activated by IL-2 and IL-15 and therefore define signaling pathways by which these T-cell growth factors may regulate gene transcription.Interleukin 2 (IL-2) is a key growth factor that induces the proliferation and functional differentiation of T lymphocytes and natural killer cells. IL-15 shares many characteristics with IL-2, such as the generation of cytotoxic T cells and lymphokine-activated killer cells (1-3). Two IL-2 receptor subunits, the , chain (p75) and the common y chain (-yc), are used by IL-15, and Yc is also shared by other cytokine receptors, including the IL-4 receptor (4, 5). Studies also suggest the existence of an IL-15 receptor subunit distinct from the IL-2 receptor subunits (3). The finding that IL-15 and IL-2 share receptor subunits and exhibit overlapping biological effects implies that they may activate common intracellular substrates but, as yet, this has not been explored.Recently, a signal transduction pathway that involves Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) has been found to be utilized by a number of growth factors and cytokines that bind members of the hematopoietin receptor family (6, 7). We and others (8-11) have cloned a member of the Janus family (JAK3) and have shown that JAK3 and JAK1 are functionally coupled to the IL-2 receptor, as well as other receptors that use 'yc (receptors for IL-4, -7, and -9). The requisite role of yc in signaling is perhaps best illustrated by the discovery that mutations of this subunit result in X chromosome-linked severe combined immunodeficiency (12). Many of these mutations disrupt JAK3-,yc interactions, suggesting that this disruption might be important in the pathogenesis of this immunodeficiency (13). Given that IL-15 shares this common receptor subunit, it was important to examine whether IL-15 might also activate JAK3 and JAK1. Studies of the mechanism by which hematopoietin receptors activate gene transcription indicate that STAT proteins become rapidly tyrosine-phosphorylated in the receptor complex and directly translocate to the nucleus, where they bind DNA and activate transcription (14...