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Transforming growth factor-β in T-cell biology

Key Points

  • Transforming growth factor-β (TGF-β) inhibits the differentiation of both CD4+ and CD8+ naive T cells into effectors. This effect is not dependent on inhibition of proliferation.

  • TGF-β blocks T helper (TH)2 development by inhibiting expression of Gata-3 (a master TH2 transcriptional activator).

  • Similarly, TGF-β might block TH1 development through inhibition of a master TH1 transcriptional activator; a candidate is T-bet (T-box expressed in T cells).

  • Early interferon-γ (IFN-γ) production by differentiating TH1 cells can protect from the inhibitory effects of TGF-β. Fully differentiated TH1 cells do not express the IFN-γ receptor are so are resistant to the protective effects of IFN-γ.

  • Fully differentiated TH2 cells are resistant to the inhibitory effects of TGF-β, but the mechanism has not been elucidated.

  • T cells activated in vitro in the presence of TGF-β resemble central memory T cells in that they retain the capacity to produce interleukin-2 (IL-2) and can differentiate to TH1 or TH2 effector cells when restimulated.

  • Blocking TGF-β signalling in T cells by using transgenic approaches leads to spontaneous T-cell activation and inflammation, indicating that TGF-β signalling in T cells is essential for T-cell homeostasis.

  • The role for TGF-β in controlling T-cell homeostasis seems to be in preventing inappropriate responses to certain self- or environmental antigens, rather than control of normal T-cell responses to low-avidity self-ligands that constitute survival signals.

  • When TGF-β signalling is blocked in T cells, inflammation is most severe at mucosal sites where exposure to environmental antigens is highest (gut and lung). Dysregulated responses to the normal gut flora have been implicated in the pathogenesis of inflammatory bowel disease.

  • Mucosal T cells from patients with inflammatory bowel disease (IBD) express high levels of Smad7, an inhibitor of TGF-β signalling, implying dysregulated TGF-β signalling might have a role in the pathogenesis of IBD.

  • A cell-surface form of TGF-β might be important for CD4+CD25+ regulatory T-cell function.

  • TGF-β released directly by apoptotic cells, or by antigen-presenting cells that have ingested apoptotic cells, might prevent T-cell responses to self-antigens.

  • TGF-β might also inhibit T cells indirectly through its inhibitory effects on antigen-presenting cells.

  • TGF-β production is associated with many tumours and might normally suppress tumour-specific T-cell responses, as blocking TGF-β signals in T cells in mice leads to the generation of potent CD8+ T-cell responses and tumour rejection.

Abstract

Strict control of T-cell homeostasis is required to permit normal immune responses and prevent undesirable self-targeted responses. Transforming growth factor-β (TGF-β) has been shown to have an essential role in that regulation. Owing to its broad expression, and inhibitory effects on multiple cell types of the immune system, TGF-β regulation is complex. Through advances in cell-specific targeting of TGF-β signalling in vivo, the role of TGF-β in T-cell regulation has become clearer. Recent in vitrostudies provide a better understanding of how TGF-β regulates T-cell homeostasis, through multiple mechanisms involving numerous cell types.

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Figure 1: Role of TGF-β in T-cell differentiation.
Figure 2: Models of how TGF-β could inhibit activation of self-reactive T-cells.
Figure 3: Inhibition of antitumour response by TGF-β.

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Correspondence to Richard A. Flavell.

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DATABASES

OMIM

Crohn's disease

IBD

LocusLink

CD2

CD4

CD44

CD45

CIITA

Gata-3

IFN-γ

IL-2

IL-4

IL-5

IL-10

IL-12

IL-12Rβ2

IL-13

LT-α

NOD2

p15

p21

p27

Rag1

Smad7

T-bet

TGF-β1

TGF-β2

TGF-β3

tumour-necrosis factor-α

FURTHER INFORMATION

Encyclopedia of Life Sciences

antigen-presenting cells

T lymphocytes (helpers)

Richard Flavell's lab

Glossary

EPIGENETIC

Epigenetics is the study of heritable changes in gene expression that occur without a change in DNA sequence.

T-BOX FAMILY

A new family of transcription factors that seems to be crucial in the development of all animal species was recently uncovered on the basis of homology of the DNA-binding domain of the Brachyury, or T locus, gene product.

GATA FAMILY

The members of the Gata family of DNA-binding proteins contribute to the transcriptional regulation of cell-lineage commitment and differentiation. Each recognizes a DNA consensus-sequence motif (T/A)GATA(A/G) through a highly conserved DNA-binding domain comprising two zinc fingers.

POSITIVE SELECTION

The process in the thymus that selects thymocytes expressing T-cell receptors (TCRs) that have the ability to interact weakly with self-MHC.

INFLAMMATORY BOWEL DISEASE

(IBD). A group of conditions, of unknown aetiology, in which the intestinal mucosa is chronically inflammed. Includes Crohn's disease and ulcerative colitis.

CLASS II TRANSACTIVATOR

(CIITA). A non-DNA-binding co-activator that functions as a master control factor for MHC class II expression.

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Gorelik, L., Flavell, R. Transforming growth factor-β in T-cell biology. Nat Rev Immunol 2, 46–53 (2002). https://doi.org/10.1038/nri704

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