| Allergic asthma is characterised by the enhanced production of allergen-specific immunoglobulin E (IgE) and eosinophilic inflammation of the airways. It is generally accepted that these features are causally related to the development and activation of allergen-specific Th2 cells, which by virtue of the secretion of the type 2 cytokines interleukin (IL)-4, IL-5 and IL-13 induce B cells to switch to immunoglobulin E (IgE) synthesis and promote the production and activation of eosinophils. Despite an enormous international effort, the exact mechanisms underlying the polarization of naive T helper cells into Th2 cells and the criteria for induction of Th2 cytokine production are not fully clear. The cytokines IL-12 (produced by antigen-presenting cells) and IL-4 are strong polarizing factors, respectively inhibiting and promoting Th2 development. However, experiments in mice have shown that disruption of the genes coding for STAT4 and/or STAT6, thus abolishing all responsiveness to IL-12 and IL-4, prevented neither Th2 nor Th1 development. This and various other lines of evidence indicate that alternative pathways of Th2 cell polarization must exist. Recently, two novel membrane-bound receptor molecules, T1/ST2 and ICOS, were shown to be exclusively and constitutively expressed by Th2 cells in the mouse. Blocking experiments in in vivo models of Th2-mediated eosinophilic airway inflammation showed that inhalation of T1/ST2-Ig or ICOS-Ig fusion proteins (preventing interaction with their putative ligands), prior to allergen challenge, strongly inhibited allergen-induced eosinophil influx and Th2 cytokine production, suggesting an important role of both molecules in the Th2 effector functions. In vitro experiments on Th cell polarization showed that at least T1/ST2 is required as well for Th2 cell development.
T1/ST2 and ICOS are also expressed on human Th cells, but information on their expression characteristics and function is scarce. In an initial comparative analysis of human Th cell clones, we recently found Th2-specific expression of T1/ST2 mRNA, suggesting that T1/ST2 protein expression may be Th2-specific, too. In the proposed project, we plan to investigate the levels and regulation of T1/ST2 and ICOS expression on human Th1 and Th2 cell lines, and to study the functional role of these molecules during Th2 polarization and the Th2 effector phase. Furthermore, a comparison will be made between cells from atopic and non-atopic individuals. If human T1/ST2 and ICOS prove to have similar functions as in the mouse, they may be useful as new diagnostic markers for allergic asthma and perhaps even as targets for therapeutic intervention. |
