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* Laboratory of Experimental Immunology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702;
Lymphocyte and Cell Biology Section, Molecular Immunology and Inflammation Branch, National Institute of Musculoskeletal Diseases, Bethesda, MD 20892; and
Departments of Biological Structure and Immunology, University of Washington, Seattle, WA 98195
In the periphery, IL-18 synergistically induces the expression of the Th1 cytokine IFN-
in the presence of IL-12 and the Th2 cytokines IL-5 and IL-13 in the presence of IL-2. Although the expression of these cytokines has been described in the thymus, their role in thymic development and function remains uncertain. We report here that freshly isolated thymocytes from C57BL/6 and BALB/c mice stimulated in vitro with IL-2-plus-IL-18 or IL-12-plus-IL-18 produce large amounts of IFN- and IL-13. Analysis of the thymic subsets, CD4–CD8– (DN), CD4+CD8+, CD4+CD8–, and CD4–CD8+ revealed that IL-18 in combination with IL-2 or IL-12 induces IFN- and IL-13 preferentially from DN cells. Moreover, DN2 and DN3 thymocytes contained more IFN-+ cells than cells in the later stage of maturation. Additionally, IL-18 in combination with IL-2 induces CCR4 (Th2-associated) and CCR5 (Th1-associated) gene expression. In contrast, IL-18-plus-IL-12 specifically induced CCR5 expression. The IL-2-plus-IL-18 or IL-12-plus-IL-18 effect on IFN- and IL-13 expression is dependent on Stat4 and NF-
B but independent of Stat6, T-bet, or NFAT. Furthermore, IL-12-plus-IL-18 induces significant thymocyte apoptosis when expressed in vivo or in vitro, and this effect is exacerbated in the absence of IFN-. IL-12-plus-IL-18-stimulated thymocytes can also induce IA-IE expression on cortical and medullary thymic epithelial cells in an IFN--dependent manner. Thus, the combination of IL-2, IL-12, and IL-18 can induce phenotypic and functional changes in thymocytes that may alter migration, differentiation, and cell death of immature T cells inside the thymus and potentially affect the Th1/Th2 bias in peripheral immune compartments.
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