Integration of Regulatory T-Cells into the Th1/Th2 Paradigm

摘要

Background: Allergy is characterized by allergen sensilizalion, driving T-cell differentiation toward Th2 phenotypc. Regulatory T-cells (T_(regs)) can control the activity and expansion of T-cells. However, the origin of the T_(regs) is unclear and therefore also the concepts to integrate T_(regs) into the Th1/h2 paradigm of T-cell differentiation. The present study describes a mechanism repressing peripheral Treg induction on the basis of the FOXP3 promoter analysis. Methods: To understand the origin of T_(regs) we investigated the promoter of the F0XP3 transcription factor, which is decisive for T_(reg) differentiation as T-BET for Th1 and GATA-3 for Th2 cells. Following localization and confirmation of the FOXP3 promoter, using reporter-gene assays, we identified regulators of the FOXP3 gene. Results: We demonstrate that cytokines such as IL-4 and TGF-beta present at the time of T-cell priming of the uncommitted cells are decisive not only in differentiating T-cells toward effector phe-notypes, but also toward T_(regs). Moreover, Th2-driving conditions that occur in allergic inflammation prevent the induction of T_(regs) by a GATA3-mediated inhibition of the FOXP3 promoter. It is demonstrated that GATA3 directly binds in the FOXP3 promoter and acts as repressor of gene transcription. Conclusion: It appears that T_(regs) require antigen-specific stimulation as Th1 or Th2 cells but differentiate only in the absence of Th1 and Th2 driving signals. T_(reg) differentiation pathways may therefore be considered as a default pathway occurring in the absence of Th1/Th2 polarizing danger signals. Thus, therapeutic establishment of allergen tolerance requires the control of inflammation to facilitate regulatory capacities of the immune system in allergic disease.