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  • Review Article
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Decision making in the immune system

The lineage decisions of helper T cells

Nature Reviews Immunology volume 2, pages 933–944 (2002)Cite this article

Key Points

  • Helper T (TH)-cell differentiation is remarkably plastic, with many extrinsic signals affecting the balance of effector subsets.

  • The role of cytokines as a purely instructive signal, causing undifferentiated cells to express new genes, is being re-examined. Among the newly recognized functions are the abilities of cytokines to mediate selective growth or survival and to repress the transcription of lineage-determining activators of the opposing fate.

  • Epigenetic effects seem to have a crucial role in organizing TH-cell differentiation. Some genes are induced by chromatin remodelling, which is a heritable trait of differentiated cells.

  • CpG demethylation of cytokine loci might be an imprinting mechanism that ensures the heritability of the expressing state.

  • Gene silencing seems to contribute to differentiation in at least two ways. The transcription of lineage-determining activator genes seems to become heritably silenced and their target cytokine loci seem to undergo physical repositioning in terminally differentiated cells of the opposing fate.

Abstract

After encountering antigen, helper T (TH) cells undergo differentiation to effector cells, which can secrete high levels of interferon-γ, interleukin-4 (IL-4), IL-10 and other immunomodulators. How TH cells acquire, and remember, new patterns of gene expression is an area of intensive investigation. The process is remarkably plastic, with cytokines being key regulators. Extrinsic signals seem to be integrated into cell-intrinsic programming, in what is becoming an intriguing story of regulated development. We summarize the latest insights into mechanisms that govern the lineage choices that are made during TH-cell responses to foreign pathogens.

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Figure 1: The original instructive model of helper T-cell differentiation.
Figure 2: Pathways for the induction of expression of IL-4.
Figure 3: Pathways for the induction of expression of IFN-γ.
Figure 4: Redundant pathways of TH2-cell development — integration at the level of GATA3 transcription.
Figure 5: Models of secondary roles for cytokines in differentiation.
Figure 6: Model of orderly derepression of the IL-4 gene.
Figure 7: Model of stages of TH1-cell induction and maturation.
Figure 8: Relationships between pathogens, the innate immune system and TH-cell development.

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Author information

Authors and Affiliations

  1. Howard Hughes Medical Institute and Department of Pathology and Immunology, Washington University School of Medicine, St Louis, 63110, Missouri, USA

    Kenneth M. Murphy

  2. Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, 19104, Philadelphia, USA

    Steven L. Reiner

Authors
  1. Kenneth M. Murphy
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  2. Steven L. Reiner
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Correspondence to Kenneth M. Murphy.

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DATABASES

LocusLink

B7H

CD28

c-MAF

Dnmt1

EBI3

FOG1

GADD45β

GADD45γ

GATA3

GATA4

GFI1

HFN3β

HLX

ICAM1

ICOS

IFN-γ

IL-4

IL-5

IL-6

IL-12

IL-12Rβ1

IL-12Rβ2

IL-13

Il-18

IL-23α

LFA1

Mbd2

MEL18

NFAT

p28

p38 MAPK

ROG

STAT1

STAT4

STAT6

T-bet

TGF-β

type I IFNs

WSX1

Glossary

EPIGENETIC

Refers to the heritable, but potentially reversible, states of gene activity that are imposed by the structure of chromatin or covalent modifications of DNA and histones.

CHROMATIN

Composed of nucleosomes, which are the basic repeating units of eukaryotic genomes. Nucleosomes consist of 146 base pairs of DNA wound around an octamer of histone proteins.

GADD-FAMILY PROTEIN

(Growth-arrest and DNA-damage inducible proteins). In response to environmental stresses, these proteins mediate activation of the p38 mitogen-activated protein kinase pathway and are involved in the regulation of growth and apoptosis.

HISTONE CODE

Refers to various post-translational modifications of histones that might impose states of gene activity or silence.

DNASE-I HYPERSENSITIVITY

Refers to sites of nuclease sensitivity when nuclei from cells are exposed to limiting concentrations of DNase I. The digested regions of DNA correspond to sites of open DNA, which might be factor-binding sites or areas of altered nucleosome conformation.

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Murphy, K., Reiner, S. The lineage decisions of helper T cells. Nat Rev Immunol 2, 933–944 (2002). https://doi.org/10.1038/nri954

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