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      Transcriptional and epigenetic regulation of T-helper lineage specification

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          Abstract

          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. In this article, we review recent studies on the transcriptional and epigenetic regulation of distinct Th cell lineages. Moreover, we review current study linking immune disease-associated single-nucleotide polymorphisms with distal regulatory elements and their potential role in the disease etiology.

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          Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.

          Daniel Cua, Jonathan P Sherlock, Yi. Chen … (2003)
          Interleukin-12 (IL-12) is a heterodimeric molecule composed of p35 and p40 subunits. Analyses in vitro have defined IL-12 as an important factor for the differentiation of naive T cells into T-helper type 1 CD4+ lymphocytes secreting interferon-gamma (refs 1, 2). Similarly, numerous studies have concluded that IL-12 is essential for T-cell-dependent immune and inflammatory responses in vivo, primarily through the use of IL-12 p40 gene-targeted mice and neutralizing antibodies against p40. The cytokine IL-23, which comprises the p40 subunit of IL-12 but a different p19 subunit, is produced predominantly by macrophages and dendritic cells, and shows activity on memory T cells. Evidence from studies of IL-23 receptor expression and IL-23 overexpression in transgenic mice suggest, however, that IL-23 may also affect macrophage function directly. Here we show, by using gene-targeted mice lacking only IL-23 and cytokine replacement studies, that the perceived central role for IL-12 in autoimmune inflammation, specifically in the brain, has been misinterpreted and that IL-23, and not IL-12, is the critical factor in this response. In addition, we show that IL-23, unlike IL-12, acts more broadly as an end-stage effector cytokine through direct actions on macrophages.
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            TET enzymes, TDG and the dynamics of DNA demethylation.

            Rahul M. Kohli, Yi Zhang (2013)
            DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.
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              T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

              Xuexian O. Yang, Bhanu P. Pappu, Roza Nurieva … (2008)
              T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the conserved noncoding sequence 2 in Il17-Il17f locus. ROR alpha deficiency resulted in reduced IL-17 expression in vitro and in vivo. Furthermore, ROR alpha and ROR gamma coexpression synergistically led to greater Th17 differentiation. Double deficiencies in ROR alpha and ROR gamma globally impaired Th17 generation and completely protected mice against experimental autoimmune encephalomyelitis. Therefore, Th17 differentiation is directed by two lineage-specific nuclear receptors, ROR alpha and ROR gamma.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Immunol Rev
                Journal ID (iso-abbrev): Immunol. Rev
                Journal ID (publisher-id): imr
                Title: Immunological Reviews
                Publisher: BlackWell Publishing Ltd (Oxford, UK )
                ISSN (Print): 0105-2896
                ISSN (Electronic): 1600-065X
                Publication date (Print): September 2014
                Publication date (Electronic): 14 August 2014
                Volume: 261
                Issue: 1
                Pages: 62-83
                Affiliations
                [1 ]Turku Centre for Biotechnology, University of Turku and Åbo Akademi University Turku, Finland
                [2 ]National Doctoral Programme in Informational and Structural Biology Turku, Finland
                [3 ]Turku Doctoral Programme of Molecular Medicine (TuDMM), University of Turku Turku, Finland
                Author notes
                Correspondence to: Riitta Lahesmaa Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, P.O. Box 123, BioCity, Turku FI-20520, Finland, Tel.: + 358-2-333 8601, Fax: + 358-2-2518808, e-mail: riitta.lahesmaa@ 123456btk.fi
                Article
                DOI: 10.1111/imr.12204
                PMC ID: 4255756
                PubMed ID: 25123277
                SO-VID: d0f9e452-f993-4d29-be11-23a3e3e1aad1
                Copyright © © 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd.
                License:

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Subject: Invited Reviews

                Keywords: t-helper cell,gene regulation,transcription factors,stats,epigenetic modification,snps
                Data availability:
                Keywords: t-helper cell, gene regulation, transcription factors, stats, epigenetic modification, snps

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