The IL-2 receptor and related cytokine receptor systems are being studied to clarify the T cell immune response in normal, neoplastic, and immunodeficient states. Following T-cell activation by antigen, the magnitude and duration of the T-cell immune response is determined by the amount of IL-2 produced, levels of receptors expressed, and time course of each event. The IL-2 receptor contains three chains, IL-2Ra, IL-2Rb, and gc. Dr. Leonard cloned IL-2Ra in 1984, we discovered IL-2Rb in 1986, and reported in 1993 that mutation of the gc chain results in X-linked severe combined immunodeficiency (XSCID, which has a T-B+NK- phenotype) in humans. We reported in 1995 that mutations of the gc-associated kinase, Jak3, result in an autosomal recessive form of SCID indistinguishable from XSCID and in 1998 that T-B+NK+ SCID results from mutations in the IL7R gene. Based on work in our lab and others, gc was previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. We also previously characterized genes that were induced or repressed by IL-2, IL-4, IL-7, and IL-15, including showing the negative regulation of the IL-7 receptor alpha chain, a finding with implications in understanding how IL-2 can promote cell death, and the positive regulation of a dual specificity phosphatase, DUSP5, that negatively regulates IL-2-mediated activation of ERK kinases. ? ? In the past year, we reported a range of genes induced by IL-2 versus IL-21, helping to explain dramatic differences in the anti-tumor actions of IL-2 versus IL-21 (see also report on IL-21). We also made substantial progress on a dual specificity phosphatase, denoted DUSP5, that is induced by IL-2 and thus an IL-2 target gene. We demonstrated that transgenic overexpression of DUSP5 results in a block in thymocyte development at the CD4/CD8 double positive stage. Moreover, DUSP5-expressing T cells show decreased IL-2-dependent proliferation and defective IL-2-mediated induction of genes, consistent with the importance of this phosphatase. Interestingly and strikingly, the transgenic mice also develop autoimmune disease, indicating a role for ERK kinases in the regulation of tolerance. Together, these findings indicate that normal regulation of DUSP5 is critical for normal immune development, actions of IL-2, and immunological tolerance.? ? Downstream of ERK kinases are ribosome S6 kinases known as Rsks. We reported that IL-2 and IL-15 but not IL-7 can activate Rsk1 and Rsk2 and generated data consistent with a critical role for Rsk2 in survival of T cells based on the use of wild type or dominant negative Rsk2. We also generated mice lacking Rsk2 and found that although they had normal lymphoid development, their T cells exhibited a delay in cell cycle progression as well as diminished production of IL-2. Thus, regulation of DUSP5 and Rsk2 are critical for normal T cell physiology.? ? The closest cytokine system to IL-2 is that of IL-15 in that both cytokines share IL-2Rb and the gc but have distinctive alpha chains. IL-15 is particularly important for NK-cell development and function and CD8+ T cell homeostasis. We studied the importance of the IL-15 receptor cytoplasmic domain. As compared to IL-2Ra, IL-15Ra has a larger cytoplasmic domain. IL-15 signals at least in part through a process known as transpresentation whereas so far this mechanism of signaling has not been shown for IL-2. To investigate the role of the IL-15Ra cytoplasmic domain, we generated a chimeric receptor molecule with the extracellular and transmembrane portions of IL-2Ra but the cytoplasmic domain of IL-15Ra and knock-in mice were generated. We performed a range of studies in cells lines and in these mice. Adoptive transfer experiments with the chimeric receptor revealed that the IL-15Ra introcytoplasmic domain is required for normal IL-15Ra function but not for transpresentation.? ? Overall, these studies help to improve our understanding of signaling by gc family cytokines. These findings clarify basic molecular mechanisms that are relevant to normal and pathological immune cell function such as allergy, autoimmunity, and cancer.
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