The enigma of CD4‐lineage specification

Xiong, Ye; Bosselut, Rémy

doi:10.1002/eji.201041098

Cited by 14 publications

(9 citation statements)

References 68 publications

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“…Our results suggest that the Cd4 locus may undergo enhancer switching in part similar to Cd8a / Cd8b1 loci, and that CD4 expression may actively be maintained by a post-selection stage-specific enhancer that requires the 1.5 kb sequence. Although transcription factor requirements for CD4 versus CD8 lineage decision have been explained in large part by Gata3, ThPOK, and Runx3/CBFβ (3, 28–30), there may be additional factors which also play key roles in the cell fate decision process presumably through regulation of sustained Cd4 expression. The putative post-selection enhancer appears likely to account for Ep4-independent CD4 expression following MHCII-restricted selection (8).…”

Section: Discussionmentioning

confidence: 99%

A Silencer-Proximal Intronic Region Is Required for Sustained CD4 Expression in Postselection Thymocytes

Henson

Chou

Sakurai

et al. 2014

The Journal of Immunology

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It has been proposed that differential kinetics of CD4/CD8 co-receptors regulate fate choice of selected thymocytes. Sustained signals by interaction between MHC class II and TCR/CD4 is required for commitment to the CD4 helper lineage. While prematurely terminated MHC-TCR/CD4 interaction in transgenic mouse models results in lineage redirection, it is unclear if CD4 expression is actively maintained by endogenous cis-elements to facilitate prolonged signaling under physiological conditions. Here we show that sustained CD4 expression in post-selection thymocytes requires an intronic sequence containing an uncharacterized DNase I hypersensitivity site (DHS) located 3’ to the silencer. Despite normal CD4 expression before selection, thymocytes lacking a 1.5 kb sequence in intron 1 including the 0.4 kb silencer and the DHS, but not the 0.4 kb silencer alone, failed to maintain CD4 expression upon positive selection and are redirected to the CD8 lineage following MHC class II-restricted selection. Furthermore, CpG dinucleotides adjacent to the DHS are hypermethylated in CD8+ T cells. These results indicate that the 1.5 kb cis-element is required in post-selection thymocytes for helper lineage commitment, presumably mediating the maintenance of CD4 expression, and suggest that inactivation of the cis-element by DNA methylation may contribute to epigenetic Cd4 silencing.

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Section: Discussionmentioning

confidence: 99%

A Silencer-Proximal Intronic Region Is Required for Sustained CD4 Expression in Postselection Thymocytes

Henson

Chou

Sakurai

et al. 2014

The Journal of Immunology

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“…In contrast to Runx3 for cytotoxic genes, it is not yet clear to which extent Thpok itself contributes to the expression of CD4-lineage genes, including its own [15, 25, 42, 43]. However, genetic studies have identified several transcription factors important for CD4 T cell generation, and thus candidates for a specification function; these include Gata3, the DNA-binding protein Tox, and E proteins E2A and HEB [44–46].…”

Section: Lineage Specificationmentioning

confidence: 99%

CD4–CD8 differentiation in the thymus: connecting circuits and building memories

Xiong

Bosselut

2012

Current Opinion in Immunology

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The proper choice of the CD4-helper or CD8-cytotoxic lineages by developing T cells is crucial for the generation of an antigen-responsive and functionally fit T cell repertoire. Here we present a brief overview of the transcriptional control of this process, with emphasis on two issues. The study of Cd4 expression, that had previously generated important paradigms for transcriptional regulation in eukaryotic cells, now brings new twists to the concept of ‘epigenetic memory’. On the other hand, connections are emerging between transcriptional regulators critical for commitment to either lineage. The present review attempts to integrate these findings and discusses the still elusive mechanisms that match CD4-CD8 lineage differentiation to MHC specificity.

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“…How TCR specificity determines thymocyte lineage fate during positive selection is best described by the kinetic signaling model 4 - 7 which proposes that lineage fate is determined by whether TCR signaling persists throughout positive selection or is disrupted, allowing positively selected thymocytes to then be signaled by cytokines. In this perspective, persistent TCR signaling induces expression of ThPOK 8 - 10 , the CD4-helper lineage-specifying transcription factor, whereas cytokine signaling induces expression of Runx3d 11 - 13 , the CD8-cytotoxic lineage-specifying factor 4 , 11 - 15 . Thus, the kinetic signaling model stipulates that CD8 lineage fate is signaled by cytokines and not by TCRs which instead signal CD4 lineage fate.…”

Section: Introductionmentioning

confidence: 99%

Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus

et al. 2017

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T cell antigen receptor (TCR) signaling in the thymus initiates positive selection but CD8 lineage fate is thought to be induced by cytokines after TCR signaling has ceased, although this remains controversial and unproven. We now identify four non-common gamma chain (γc) receptor-signaling cytokines (IL-6, IFN-γ, TSLP, TGF-β) that, like IL-7 and IL-15, induce expression of the lineage-specifying transcription factor Runx3d and signal the generation of CD8 T cells. Remarkably, elimination of in vivo signaling by all ‘lineage-specifying cytokines’ during positive selection eliminated Runx3d expression and completely abrogated CD8 single-positive thymocyte generation. Thus, this study proves that signaling during positive selection by lineage-specifying cytokines is responsible for all CD8 lineage fate decisions in the thymus.

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The enigma of CD4‐lineage specification

Cited by 14 publications

References 68 publications

A Silencer-Proximal Intronic Region Is Required for Sustained CD4 Expression in Postselection Thymocytes

A Silencer-Proximal Intronic Region Is Required for Sustained CD4 Expression in Postselection Thymocytes

CD4–CD8 differentiation in the thymus: connecting circuits and building memories

Identification of lineage-specifying cytokines that signal all CD8+-cytotoxic-lineage-fate 'decisions' in the thymus

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