The human 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, his group 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; 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 this lab and others, gc was shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. In the past year, genes induced and repressed by IL-2, IL-4, IL-7, and IL-15 were identified and two were characterized in detail. It was reported that IL-2 negatively regulates expression of the IL-7 receptor alpha chain expression, a finding with potential major implications in understanding how IL-2 can promote cell death as well as repression. The mechanism of IL-7-mediated repression depends on PI 3-kinase and Akt. Moreover, a genome wide analysis of regulated genes revealed IL-2, IL-7, and IL-15 regulated a very similar set of genes whereas IL-4 regulated a distinctive set. This likely relates to the activation of Stat5 proteins by IL-2, IL-7, and IL-15 and predominant activation of Stat6 by IL-4. A dual specificity phosphatase, DUSP5 was characterized in detail as an IL-2-induced gene. Interesting, DUSP5 negatively regulates activation of ERK kinases by IL-2, suggesting that IL-2-mediated activation of DUSP5 is a negative regulatory pathway for controlling IL-2-mediated ERK activation. The identification of a major serine phosphorylation site of Stat5a was also reported. Interesting, this phosphorylation did not exert a positive effect as has been found for other STAT proteins; instead, if anything, the effect could be negative. The group continued its effort to study TSLP, whose binding protein, TSPLR is most related to gc. The group previously published the cloning of the IL-21 receptor. In the past year, the lab reported the creation of IL-21R knockout mice and demonstrated that IL-21 plays a critical role in regulating immunoglobluin production. Interestingly, IL-21 appears to negatively regulate IgE production, whereas it is essential for IgG1 production and studies also using IL-4 KO mice reveal that IL-4 and IL-21 together globally regulate immunoglobulin production. Whereas previous work indicated that defective IL-7 signaling explained the T-cell defect in XSCID and defective IL-15 signaling explained the NK cell defect in XSCID, these studies indicate that a combination of defects in IL-4 and IL-21 signaling explain the B cell defects in XSCID and in Jak3-deficient SCID. Overall, these studies help to aspects of signaling by IL-2 and related cytokines. These findings have relevance to immunodeficiency and the control of T-cell growth.
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