Analysis of interleukin-4 and of interleukin-13 in immunity to Cryptococcus neoformans using cell-specific gene-deficient mice
Final Report Abstract
The results of the current study show the two sides of IL-4R signaling pathway. In the early phase of pulmonary cryptococcosis IL-4R supports the transient protection by inducing Th1-dependent classical activation of macrophages (besides enhancing the recruitment of macrophages and DC to the lung). These macrophages are able to control infection by NO secretion. In contrast to this early beneficial role of IL-4R, in the late phase of infection the IL-4R mediates detrimental induction of Th2 cells with concomitant alternative activation of macrophages which are no longer able to control fungal growth but support propagation of the pathogen. Via IL-4R and IL-33R Th2 cells become polyfunctional and produce large amounts of Th2 cytokines acting especially on macrophages and also on eosinophils and goblet cells. The main axis in this plot is the Th2 cell/alternatively activated macrophage axis as shown here. Without IL-4R expression on Th cells the mouse can survive cryptococcosis and controls fungal dissemination. Even more important, without IL-4R expression on macrophages, even in an unaltered Th2 environment, mice can control the infection and become resistant. Therefore, two target cells can be postulated for possible novel therapies against cryptococcosis. By modulation of Th cells to a more Th1 phenotype cryptococcosis could be controlled. But the major effector cell in cryptococcosis is the macrophage. Modulating this single cell type can turn the whole plot from susceptibility and mortality to resistance and survival (even if there remains persistent low-level infection).
Publications
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Lack of IL-4 receptor expression on T helper cells reduces T helper 2 cell polyfunctionality and confers resistance in allergic bronchopulmonary mycosis. Mucosal Immunol. 2012 May; 5(3):299-310
Müller U, Piehler D, Stenzel W, Köhler G, Frey O, Held J, Grahnert A, Richter T, Eschke M, Kamradt T, Brombacher F, Alber G
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Abrogation of IL-4 receptor-α-dependent alternatively activated macrophages is sufficient to confer resistance against pulmonary cryptococcosis despite an ongoing Th2 response. Int. Immunol. 2013 Aug.; 25(8):459-70
Müller U, Stenzel W, Piehler D, Grahnert A, Protschka M, Köhler G, Frey O, Held J, Richter T, Eschke M, Kamradt T, Brombacher F, Alber G
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T1/ST2 promotes T helper 2 cell activation and polyfunctionality in bronchopulmonary mycosis. Mucosal Immunol. 2013 Mar; 6(2):405-14
Piehler D, Grahnert A, Eschke M, Richter T, Köhler G, Stenzel W, Alber G
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IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection. PLoS One 2014 Jan.; 9(1):e87341
Grahnert A, Richter T, Piehler D, Eschke M, Schulze B, Müller U, Protschka M, Köhler G, Sabat R, Brombacher F, G Alber
