Th2 cells regulate both humoral and cell-mediated inflammatory responses to helminth pathogens as well as toxins and other foreign soluble molecules (1
). In genetically predisposed individuals, Th2 cells also mediate atopic responses to normally innocuous materials such as animal dander, pollens, and pollutants. Th2 cells mediate these processes through the selective secretion of a subset of cytokines that include IL-4, IL-5, IL-13, and in some cases IL-9 and IL-10 (2
). Together, these cytokines lead to a cascade of events that culminate in driving inflammation at sites of allergen contact, such as the lungs in cases of allergic asthma.
Various signals contribute to a “Th2 environment” such as thymic stromal lymphopoietin (TSLP), OX40L, Notch (3
), and IL-25 (4
); however, IL-4 remains the key signal that directly drives Th2 commitment. IL-4 receptor signaling promotes STAT6 recruitment and phosphorylation (5
), which ultimately regulates induction of GATA3 transcription (6
). GATA3 is a member of the 2-zinc finger GATA-binding family of transcription factors, and its expression is critical for both T cell thymic development and Th2 commitment (7
). Once induced by IL-4, the GATA3 protein positively regulates Th2 cytokine gene expression and negatively regulates various aspects of Th1 commitment such as inhibiting the expression of the IL-12Rβ2 subunit (8
). Further, GATA3 positively regulates its own expression through an auto-activation loop, thereby maintaining Th2 stability in the absence of further IL-4 signaling (9
). The inherent stability of Th2 cells poses a significant challenge to treating allergic diseases. However, in this study, we have found that type I interferon (IFN-α/β) potently inhibits IL-4-driven Th2 commitment in human CD4+ T cells and destabilizes the Th2 phenotype by inhibiting GATA3 expression. Considering that IFN-α/β is used routinely to treat various diseases including multiple sclerosis and hepatitis C, we propose that IFN-α/β may represent a novel and readily available therapy for atopic conditions such as allergic asthma.