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Decision making in the immune system

Chromatin and CD4, CD8A and CD8B gene expression during thymic differentiation

Nature Reviews Immunology volume 2, pages 909–919 (2002)Cite this article

An Erratum to this article was published on 01 January 2003

Key Points

  • During T-cell development, immature double-positive (DP) CD4+CD8+ thymocytes develop mainly into two subsets of T cell — MHC class-II-restricted CD4+ helper T cells and MHC class-I-restricted CD8+ cytotoxic T cells.

  • Factors that are involved in the transcriptional regulation of CD4, and CD8A and CD8B genes might be involved in directing the cell fate of a DP thymocyte towards either lineage.

  • Cis elements (such as promoters and enhancers) and trans elements (such as transcription factors and chromatin-remodelling complexes) contribute to the generation of chromatin structures that control the complex pattern of CD4, CD8A and CD8B gene expression.

  • The CD4 locus includes promoter, enhancer and silencer elements that regulate CD4 gene expression. The CD8A and CD8B gene complex is outlined, and CD8 regulatory elements and enhancer-binding factors are discussed. Does a CD8 silencer exist?

  • Modifications of cis- and trans-acting elements influence the chromatin structure of the CD4, CD8A and CD8B loci, including DNA methylation and histone acetylation. Other nuclear proteins, including high-mobility group (HMG)-box-containing proteins and Ikaros are involved also.

Abstract

The regulation of gene expression during thymocyte development provides an ideal experimental system to study lineage-commitment processes. In particular, expression of the CD4, CD8A and CD8B genes seems to correlate well with the cell-fate decisions that are taken by thymocytes, and elucidating the molecular mechanisms that underlie the differential expression of these genes could reveal key events in differentiation processes. Here, we review examples of how gene cis elements (such as promoters, enhancers and locus control regions) and trans elements (such as transcription factors, chromatin-remodelling complexes and histone-modification enzymes) come together to orchestrate a finely tuned sequence of events that results in the complex pattern of CD4, CD8A and CD8B gene expression that is observed during thymocyte development.

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Figure 1: A simple model of T-cell development.
Figure 2: Chromatin remodelling.
Figure 3: The mouse Cd4 locus: transgenic constructs and silencer deletions.
Figure 4: The mouse Cd8a and Cd8b gene complex: transgenic constructs and enhancer deletions.
Figure 5: Possible chromatin states of CD4, CD8A and CD8B during thymocyte differentiation.

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Acknowledgements

We wish to apologize to those colleagues whose original work could not be discussed owing to space limitations. We also thank our colleagues A. Cerwenka, A. O'Garra, G. Stockinger, V. Tybulewicz and R. Zamoyska for comments and suggestions on the manuscript. Work in the laboratory of D.K. is supported by the Medical Research Council, UK, the Leukaemia Research Fund, UK, and the European Union; work in the laboratory of W.E. is supported by the START programme and a research grant from the Austrian Research Fund, the Austrian Academies of Sciences, and by the BMT Vienna.

Author information

Authors and Affiliations

  1. Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, London, NW7 1AA, UK

    Dimitris Kioussis

  2. Institute of Immunology, University of Vienna, Brunner Straβe 59, Vienna, 1235, Austria

    Wilfried Ellmeier

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Related links

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DATABASES

LocusLink

BAF57

BRG1

CD4

CD8A

CD8B

CD25

CD44

DNase I

DNMT1

E2A

H1

H2A

H2B

H3

H4

HAT

hBRM

HDAC1

HEB

Ikaros

LAG3

LEF1

RUNX1

RUNX3

SAF

SATB1

TCF1

TOX

Glossary

PROMOTER

The regulatory region of DNA to which RNA polymerase binds to initiate transcription.

ENHANCER

A control element to which regulatory proteins bind, thereby influencing the rate of gene transcription. Enhancers function in an orientation- and position-independent manner (they can act either upstream or downstream of a gene, or in an intron).

EUCHROMATIN

Low-density (as defined by electron microscopy) regions in the nucleus that are thought to contain open chromatin structures associated with the active transcription of genes.

HETEROCHROMATIN

High-density regions in the nucleus that are thought to contain compacted chromatin structures associated with silent genes.

DNASE-I-HYPERSENSITIVITY SITES

(DH sites). Areas of the genome that are thought to have an open chromatin configuration and are, therefore, accessible to DNase I.

EPIGENETIC

Any heritable influence (in the progeny of cells or of individuals) on chromosome or gene function that is not accompanied by a change in DNA sequence. Examples of epigenetic events include mammalian X-chromosome inactivation, imprinting, centromere inactivation and position effect variegation.

HISTONE DEACETYLASE

(HDAC). An enzyme that removes acetyl groups from histone tails.

HISTONE ACETYLTRANSFERASE

(HAT). An enzyme that adds acetyl groups to histone tails.

SILENCERS

DNA elements that repress promoter and/or enhancer activity in a position- and orientation-independent manner, possibly by influencing chromatin structure.

POSITION EFECT VARIEGATION

(PEV). A phenomenon in which a gene is activated in only a proportion of cells in the lineage in which it is normally expressed, owing to the proximity of heterochromatin.

LOCUS CONTROL REGION

(LCR). A gene-regulatory element that allows position-independent, copy-number-dependent and tissue-specific expression of transgenes.

CRE RECOMBINASE

Cre is a site-specific recombinase that recognizes and binds specific sites known as loxP. Two loxP sites recombine in the presence of Cre, allowing DNA that is cloned between two such sites to be removed by Cre-mediated recombination.

MATRIX-ATTACHMENT REGIONS

(MARs). DNA elements that are thought to tether loops of chromatin to specific sites in the nucleoplasm.

DNA METHYLTRANSFERASE 1

(DNMT1). An enzyme that maintains the methylation state of DNA during replication.

SATB1

(special AT-rich binding protein 1). A nuclear protein that recognizes double-stranded DNA with a high base-unpairing propensity and associates with matrix-attachment regions.

HIGH-MOBILITY GROUP BOX

(HMG box). A protein domain (found in many proteins of this family) that binds DNA and causes bending of its backbone.

BAF

(BRG- or hBRM-associated factor complex). One of several SWI/SNF-like chromatin-remodelling complexes in mammals.

SWI/SNF COMPLEX

A chromatin-remodelling multiprotein complex that was identified initially in yeast. Related complexes exist in mammals and are involved in remodelling the chromatin of various genes.

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Kioussis, D., Ellmeier, W. Chromatin and CD4, CD8A and CD8B gene expression during thymic differentiation. Nat Rev Immunol 2, 909–919 (2002). https://doi.org/10.1038/nri952

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