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* Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland;
Graduate School of Biomedical Sciences, University of Turku, Turku, Finland;
The National Graduate School in Informational and Structural Biology, Åbo Akademi University, Turku, Finland; and
Drug Discovery Graduate School, University of Turku, Turku, Finland
Th cell subtypes, Th1 and Th2, are involved in the pathogenesis or progression of many immune-mediated diseases, such as type 1 diabetes and asthma, respectively. Defining the molecular networks and factors that direct Th1 and Th2 cell differentiation will help to understand the pathogenic mechanisms causing these diseases. Some of the key factors regulating this differentiation have been identified, however, they alone do not explain the process in detail. To identify novel factors directing the early differentiation, we have studied the transcriptomes of human Th1 and Th2 cells after 2, 6, and 48 h of polarization at the genome scale. Based on our current and previous studies, 288 genes or expressed sequence tags, representing 
1–1.5% of the human genome, are regulated in the process during the first 2 days. These transcriptional profiles revealed genes coding for components of certain pathways, such as RAS oncogene family and G protein-coupled receptor signaling, to be differentially regulated during the early Th1 and Th2 cell differentiation. Importantly, numerous novel genes with unknown functions were identified. By using short-hairpin RNA knockdown, we show that a subset of these genes is regulated by IL-4 through STAT6 signaling. Furthermore, we demonstrate that one of the IL-4 regulated genes, NDFIP2, promotes IFN-
production by the polarized human Th1 lymphocytes. Among the novel genes identified, there may be many factors that play a crucial role in the regulation of the differentiation process together with the previously known factors and are potential targets for developing therapeutics to modulate Th1 and Th2 responses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Academy of Finland, Sigrid Jusélius Foundation, National Technology Agency of Finland, Turku Graduate School of Biomedical Sciences, National Graduate School in Informational and Structural Biology, Drug Discovery Graduate School, Ida Montin Foundation, Finnish Society of Allergology and Immunology, Pulmonary Association Heli, Jenny and Antti Wihuri Foundation, Väinö and Laina Kivi Foundation, Allergy Research Foundation of South-Western Finland, and Turku University Hospital Fund.
2 R.J.L. and M.L. made an equal contribution to this work.
3 Address correspondence and reprint requests to Prof. Riitta Lahesmaa, Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, P.O. Box 123, FIN-20521, Turku, Finland. E-mail address: riitta.lahesmaa{at}btk.fi
4 Abbreviations used in this paper: EST, expressed sequence tag; CT, threshold cycle; shRNA, short-hairpin RNA.
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