Combined with TCR stimuli, extracellular cytokine signals initiate the differentiation of naive CD4+ T cells into specialized effector T-helper (Th) and regulatory T (Treg) cell subsets. lineages. At the later stage of Th1 cell differentiation, T-betCBCL6 complex represses transcription to keep the production of IFN- in control as excessive production of IFN- could cause autoimmunity 113. RUNX3 actually interacts with T-bet to activate transcription by binding to its promoter and inhibits transcription of cytokine by binding to its silencer region 111. Interestingly it was recently reported that T-bet and RUNX (RUNX1 and RUNX3) are also needed for transcription in IFN-producing Th17 Cells 114. Moreover, T-bet interacts with GATA3 (GATA-binding protein 3) to inhibit transcription of Th2 cytokine genes and block Th2 development 115,116. In addition, recent genome-wide studies have revealed that T-bet and GATA3 S63845 regulate the fate of the alternative cell lineages through a shared set of target genes 117,118. T-bet also blocks the differentiation of Th17 cell lineage by inhibiting RUNX1-mediated activation of RORC, a grasp regulator of Th17 differentiation 119,120. A recent study showed that T-bet inhibits the interferon regulatory factor 4 (IRF4) expression to repress Th17 cell lineage 121. Several other TFs have also been shown to regulate Th1 differentiation. TFs, ATF2, and ATF3 were reported to bind at kinase family genes are induced by Th1-polarizing cytokines, indicating their role in regulation of Th1 cell differentiation 124. Further we have shown that PIM kinases promote Th1 differentiation by upregulating both pathways 125. Transcriptional control of Th2 cell differentiation Combined with TCR-induced signals, IL4 initiates Th2 cell differentiation by phosphorylating STAT6, which then translocates to the nucleus and activates transcription of its target genes. These include and genes, the key cytokine and TF, respectively, needed for Th2 cell lineage specification. S63845 STAT6 is essential for Th2 differentiation as its genetic deletion severely hampers Th2 cell differentiation 126. STAT6 enforces GATA3 expression by exchanging the PcG complex with the TrxG complex at the genetic locus of locus to boost IL4 production in Th2 cells 131. In Th2 cells, global mapping of STAT3 binding revealed that STAT3 shares several binding sites at the regulatory sites of the target genes with STAT6 in differentiating Th2 cells 97. Therefore besides STAT6, both STAT3 and STAT5 are involved in positively or negatively regulating Th2 cell differentiation. GATA3 is usually a lineage-specific important regulator of Th2 cell differentiation that auto-regulates its own expression by binding to its regulatory elements to further amplify Th2 differentiation. Genetic deletion of completely abolishes Th2 differentiation both and and genes 132. GATA3 promotes Th2 differentiation and maintains the cellular identity through unique mechanismsGATA3 induces transcription of Th2-specific cytokine genes (genes) itself through interacting with co-factors, and by inducing epigenetic modifications 133,134. Recent reports on genome-wide mapping of GATA3-binding sites suggested that GATA3 DXS1692E directly controls the expression of a large number of genes involved in Th2 differentiation 135,136. In addition, analysis of GATA3 binding from 10 developmental and effector T-cell lineages has revealed lineage specific as well as shared binding sites of GATA3 among different T cells. Binding of GATA3 to shared binding sites in unique T-cell subsets suggests that cofactors binding along with GATA3 are important for determining the lineage specificity. 136. For instance, GATA3 cooperates with STAT6 for its binding to regulatory sites of its target genes in S63845 Th2 cells 135. GATA3 also functions as repressor of transcription of genes important for lineage specification and commitment of the alternative Th-cell lineages 117. For example, S63845 physical conversation of GATA3 with T-bet prospects to repression of Th1 differentiation by inhibiting the transcription of and genes 115,117. Moreover, GATA3 also interacts with RUNX3 to suppress Th1 differentiation. RUNX3 in turn cooperates with T-bet for binding the promoter and silencer regions to induce IFN- production, and suppress IL4 production 137. Recently, GATA3 was shown to interact with RuvB-like protein 2 (Ruvbl2) to facilitate the proliferation of Th2 cells through suppressing the expression of a CDK inhibitor, cyclin-dependent kinase inhibitor 2c (Cdkn2c) which is a crucial regulator of cell cycle 138. Furthermore, GATA3 mediates remodeling of chromatin structure.