PU.1 is required for generating the IL-9-producing Th9 phenotype (99.10)

Abstract IL-9 secreting Th9 cells are a newly defined subset of CD4 T cells that differentiate in the presence of TGF-β and IL-4, and that we have found have increased expression of the transcription factor PU.1. In a cohort study on infants with dermatitis, we found cultured PBMCs from atopic patients secreted higher level of IL-9 than non-atopic patients following anti-CD3 stimulation. In addition, specific cat or mite allergen stimulation of these PBMCs resulted in higher IL-9 production in cultures from atopic patients than from non-atopic patients. To investigate the underlying mechanism of IL-9 production and the development of Th9 cells in human allergic disease, we differentiated Th9 cells from naïve CD4 T cells isolated from atopic and non-atopic groups. We found that, after differentiation, Th9 cells from atopic patients have higher expression of PU.1 and IL-9 than those from non-atopic patients. Moreover, atopic samples showed increased pSTAT6 levels during differentiation, compared to samples from non-atopic patients. To determine if PU.1 is a regulator of the Th9 phenotype, we transfected Th9 cultures from normal human PBMCs with PU.1-specific siRNA. Our data showed that decreasing PU.1 expression impaired IL-9 production. In conclusion, these data demonstrate a critical role of PU.1 in the regulation of Th9 differentiation and suggest that PU.1-expressing Th9 cells may be involved in human allergic disease.