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  • Review Article
  • Published:

CD4/CD8-lineage differentiation in the thymus: from nuclear effectors to membrane signals

Nature Reviews Immunology volume 4, pages 529–540 (2004)Cite this article

Key Points

  • Lineage-specific expression of the CD8 genes is achieved through multiple lineage-specific enhancer elements that are located in the CD8 locus.

  • The lineage specificity of CD4 expression is mediated by a silencer that suppresses CD4 expression in the most immature thymocyte populations and during CD8+ T-cell differentiation. Although required to establish silencing in the thymus, the CD4 silencer is not required to maintain silencing in mature CD8+ T cells.

  • Two RUNX (Runt-related transcription factor)-family proteins bind to the CD4 silencer and are essential to its function: RUNX1 promotes CD4 repression in early thymocytes, whereas RUNX3 promotes CD4 silencing during CD8-lineage differentiation.

  • The induction of CD4 silencing seems to involve many components of the transcription apparatus, including sequence-specific transcription factors such as RUNX3 and chromatin-modifying enzymes.

  • RUNX proteins are important for other aspects of CD8+ T-cell differentiation but do not seem to be required for CD8-lineage choice.

  • The transcription factor GATA3 is required for CD4+ but not CD8+ Tcell differentiation; it is still unclear whether it is involved in CD4-lineage choice or at a later stage of CD4+ T-cell development.

  • The duration of T-cell receptor (TCR) signalling during T-cell development is a crucial determinant of lineage choice: persistent signals promote CD4-lineage choice,whereas transient signals promote CD8-lineage choice.

  • The duration of TCR signalling in thymocytes affects the expression of nuclear effectors of lineage differentiation, as persistent TCR signals are required for the upregulation of GATA3 expression but not for RUNX3 expression.

Abstract

During thymocyte development, immature thymocytes that express both CD4 and CD8 genes must choose either a helper CD4+ or cytotoxic CD8+ T-cell fate. Over the past two years, there have been some important advances regarding T-cell lineage choice, including the identification of transcription factors required for CD4 gene silencing by CD8-lineage cells (RUNX3) or for CD4+ T-cell differentiation (GATA3), and a better understanding of how T-cell receptor (TCR) signalling correlates CD4/CD8-lineage differentiation to MHC specificity. This review summarizes these recent advances and highlights potential links between TCR signals and nuclear effectors of lineage differentiation.

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Figure 1: A simplified model of intrathymic differentiation.
Figure 2: Cis-regulatory elements that control CD8 gene expression.
Figure 3: Cis-regulatory elements controlling CD4 gene expression.
Figure 4: Model for the establishment of silencing in CD8-lineage thymocytes.
Figure 5: Matching lineage differentiation to MHC specificity during positive selection.

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Acknowledgements

I apologize to colleagues whose work could not be mentioned or cited because of space limitations. I am grateful to A. Singer and A. Bhandoola for continued and invaluable exchange of ideas about issues discussed in this review. I thank W. Ellmeier, X. Liu and S. Sarafova for helpful discussions, and J. Ashwell, A. Bhandoola, A. Gégonne and A. Singer for critical reading of the manuscript. Work in my laboratory is funded by the National Cancer Institute.

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  1. Laboratory of Immune Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Rémy Bosselut

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DATABASES

Entrez Gene

CD4

CD8

GATA3

HES1

HP1

LCK

MYB

Notch-1

Notch-2

RUNX1

RUNX2

RUNX3

STAT6

TOX

ZAP70

Glossary

POSITIVE SELECTION

A process in the thymus that selects thymocytes expressing T-cell receptors (TCRs) that are of intermediate avidity for self-peptide–MHC complexes. TCR signals generated by this weak interaction cause thymocyte survival and differentiation into mature T cells, the TCRs of which can recognize foreign peptides bound to self-MHC molecules. Positive selection establishes the MHC-restricted T-cell repertoire.

CIS-REGULATORY ELEMENTS

DNA sequences located within or next to transcribed genes and that either increase (enhancers) or decrease (repressor or silencer, depending on their mechanism of action) gene transcription. Cis-regulatory elements act by recruiting trans-acting transcriptional activator or repressor proteins.

ENHANCERS

Control elements within DNA to which regulatory proteins bind, thereby influencing the rate of gene transcription; enhancers function in an orientation- and position-independent manner (that is, they can act either upstream or downstream of or in an intron).

VARIEGATED

A phenomenon characterized by the expression of a gene by only a fraction of the cells, apparently randomly chosen, in a population of cells that are otherwise of the same developmental and functional status. Variegation is thought to reflect 'all-or-nothing' changes in chromatin organization.

KNOCKED-IN MUTATIONS

Mutations introduced into a gene locus using homologous recombination techniques. Unlike knockout mutations, which use large deletions or insertions to eliminate the function of the target gene, knock-in mutations are intended to change the function of the target locus, generally through point mutation.

HEMIZYGOUS

A genotype characterized by the presence of a wild-type and a non-functional allele.

THYMIC ORGAN CULTURES

A technique allowing the culture of thymic lobes taken from fetal or neonatal mice. Thymic organ culture does not disrupt thymocyte–stromal-cell interactions and allows manipulation of the extracellular milieu in which thymocytes develop, thereby combining advantages of in vivo and in vitro approaches.

CHROMATIN-REMODELLING COMPLEXES

ATP-dependent multi-protein complexes that mediate the repositioning or reorganization of nucleosomes over a single- or multi-gene locus, resulting in either increased or reduced gene transcription.

CHROMATIN IMMUNOPRECIPITATION ASSAYS

A technique allowing the detection of in vivo interactions between a DNA-associated protein and candidate DNA target sequences. It involves the fragmentation of genomic DNA chromatin after chemical crosslinking of proteins to DNA, the immunoprecipitation of protein–DNA complexes using an antibody against the protein of interest, followed by PCR amplification of candidate DNA sequences after reversal of the crosslink.

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.

RNA INTERFERENCE

A technique to inhibit (or 'knock-down') the expression of a specific target gene using short oligonucleotides that are complementary to the sequence of the gene mRNA.

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Bosselut, R. CD4/CD8-lineage differentiation in the thymus: from nuclear effectors to membrane signals. Nat Rev Immunol 4, 529–540 (2004). https://doi.org/10.1038/nri1392

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