Transcriptional and epigenetic regulation of T-helper lineage specification.
Bottom Line: 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.The lineage specification and commitment process occurs through the combinatorial action of multiple transcription factors (TFs) and epigenetic mechanisms that drive lineage-specific gene expression programs.Moreover, we review current study linking immune disease-associated single-nucleotide polymorphisms with distal regulatory elements and their potential role in the disease etiology.
Affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; National Doctoral Programme in Informational and Structural Biology, Turku, Finland; Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku, Turku, Finland.Show MeSH
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Mentions: The first determining factor that contributes to the CD4+ T-cell specificationinto a specialized Th or Treg cell is TCR stimulation. Strong TCR signal favors Th1, Th17, and Tfhcell differentiation, while weak TCR signal promotes development of Th2 cells and induced Treg cells(iTreg) 88–91.TCR-induced pioneer factors work in coordination to pass TCR-induced signal which together withother signals participate in CD4+ T-cell specification. However, how TCR-derivedpioneer factors dictate differentiation of various subtypes is not fully understood. In addition tothe TCR-induced pioneer factors, cytokine environment that stimulated T cell is an important factorfor determining the fate of a specific T-cell lineage. The cytokines secreted by APCs mainly signalthrough Type I/II cytokine receptor superfamily that uses Janus kinase–signal transducer andactivator of transcription (JAK–STAT) signaling pathway to convert cytokine-guidedenvironmental signals into intrinsic signals that initiate specific gene expression program 92. STATs are DNA-binding regulatory proteins which upon cytokinestimulation function as TFs to drive selective gene expression program that determines specificationof a relevant Th-cell subset. There are seven members in the STAT family (STAT1-4, 5 a & b,and 6) which are expressed in different Th-cell subsets and drive their differentiation uponstimulation with a given cytokine 93,94. Notably, there may be multiple cytokines that activate number of STATs involvedin the initiation of differentiation of a given Th-cell subset 12. For example, STAT1 and STAT4 become activated in Th1 cells, STAT6 in Th2 and Th9 cells,STAT3 in Th17 and Tfh cells, and STAT5 in Treg cells (Fig. 3). STAT5, activated by proliferation factor IL2, contributes todifferentiation of Th1 and Th2 cells 95,96. Importance of IL6-induced STAT3 in Th2 cell differentiation has also beenreported 97. STATs provide lineage specificity by promotingthe differentiation of a given Th-cell subset while opposing the differentiation to alternativeTh-cell subsets. For example, STAT4 promotes Th1 differentiation while inhibiting Th2differentiation. On the contrary, STAT6 drives Th2 cell differentiation and inhibits Th1 cellspecification 8. STAT5 in turn is a positive regulator of Th1,Th2, and Treg cell differentiation, while it negatively regulates differentiation of Th17 and Tfhcells 98–100.STAT3 promotes Th17 differentiation, but represses development of iTreg cells 101. Thus, STAT5 and STAT3 have opposing roles in regulating Th17 and Treg cells.Thus, STATs suppress the cell from differentiating to other T-cell lineages by directly competingwith activators and recruiting other factors promoting the expression of repressive TFs.
Affiliation: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland; National Doctoral Programme in Informational and Structural Biology, Turku, Finland; Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku, Turku, Finland.