Genome-wide identification of novel genes involved in early Th1 and Th2 cell differentiation.
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 approximately 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-gamma 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.
Lund
Riikka J
RJ
Centre for Biotechnology, University of Turku and Abo Akademi University, FIN-20521 Turku, Finland.
Löytömäki
Maritta
M
Naumanen
Tiina
T
Dixon
Craig
C
Chen
Zhi
Z
Ahlfors
Helena
H
Tuomela
Soile
S
Tahvanainen
Johanna
J
Scheinin
Joonas
J
Henttinen
Tiina
T
Rasool
Omid
O
Lahesmaa
Riitta
R
D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D015894:Genome, Human / Q000502:physiology*; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050800:STAT6 Transcription Factor / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D018417:Th1 Cells / Q000502:physiology*; D018418:Th2 Cells / Q000502:physiology*; D013997:Time Factors; D014158:Transcription, Genetic / Q000502:physiology*
C508598:IL4 protein, human; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4