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 previously shown to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Interestingly, in the previous year, genes induced and repressed by IL-2, IL-4, IL-7, and IL-15 were identified and two were characterized in detail. IL-2 was shown to negatively regulate 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. In prior work, the group also had identified and studied thymic stromal lymphopoeitin, or TSLP, whose binding protein, TSPLR is most related to gc. The group showed the previous year that although both TSLP and IL-7 share the IL-7 receptor alpha chain, the function of TSLP and IL-7 are distinctive. In particular, the group reported that mouse TSLP plays a distinctive role in CD4 T cell development whereas other cytokines that share gc, such as IL-7 and IL-15, favor the development of CD8 T cells. In the current year covered by this report, the group not only extended its studies on TSLP but also major discovery and reported that TSLP plays a critical role in the develop of asthma in a mouse model system. Finally, the group had previously published the cloning of the IL-21 receptor and had created IL-21R knockout mice and demonstrated that IL-21 plays a critical role in regulating immunoglobluin production. In the year covered by this report, the group used IL-21 transgenic mice and the method of hydrodynamic electroporation to learn more about the biology of IL-21. The group used these and in vitro systems to identify and report that IL-21 has major actions related to mediating B-cell apoptosis and the ability to critically drive the development of memory B cells and terminal differentiation into plasma cells. Moreover, it was reported that IL-21 may contribute to the pathogenesis of a murine model of systemic lupus erythematosis. The group also discovered and reported that IL-21 potently cooperates with either IL-7 or IL-15 to augment the expansion of CD8+ T cells and that this is functional in terms of potently augmenting anti-tumor effects in a murine model of melanoma. Overall, these studies help to aspects of signaling by IL-2 and related cytokines. These findings have relevance to immunodeficiency, autoimmunity, and cancer, as well as to the basic control of T-cell and B-cell actions.
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