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TGFβ signalling in control of T-cell-mediated self-reactivity

Nature Reviews Immunology volume 7, pages 443–453 (2007)Cite this article

Key Points

  • Transforming growth factor-β1 (TGFβ1) signalling is a versatile mechanism regulating cellular differentiation, maintenance and function through an elaborate network of positive and negative regulators.

  • TGFβ1 signalling in the immune system affects multiple cell types and is required for immune homeostasis.

  • Although a role for TGFβ1 signalling during thymic development is not entirely clear, TGFβ1 signalling is essential for the differentiation of natural killer T cells.

  • In the periphery, TGFβ1 signalling is essential to limit the differentiation of CD8+ and CD4+ T cells into cytolytic and T helper 1 (TH1) effector cells, respectively, through mothers against decapentaplegic homologue (SMAD)-dependent transcriptional repression of several genes encoding effector molecules.

  • Mice with a deficiency in TGFβ1 signalling in T cells exhibit an aggressive autoimmune syndrome similar to that observed in TGFβ1-deficient mice.

  • TGFβ1 signalling is not required for the differentiation of regulatory forkhead box P3 (FOXP3)+ T cells in the thymus, but is involved in the maintenance of peripheral regulatory T-cell subsets.

Abstract

In the immune system, transforming growth factor-β (TGFβ) affects multiple cell lineages by either promoting or opposing their differentiation, survival and proliferation. Understanding the cellular mechanisms of TGFβ-mediated regulation is complicated due to a broad distribution of TGFβ receptors on the surface of different immune-cell types. Recent studies using in vivo genetic approaches revealed a critical role for TGFβ signalling in T cells in restraining fatal autoimmune lesions. Here, we review recent advances in our understanding of a role for TGFβ signalling in the regulation of T-cell differentiation in the thymus and in the periphery, with a particular emphasis on TGFβ-mediated control of self-reactive T cells.

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Figure 1: TGFβ signalling affects all populations of leukocytes in a stimulatory or inhibitory manner.
Figure 2: A schematic of the TGFβ1 signalling cascade from the cell membrane to the nucleus.
Figure 3: A role for TGFβ1 signalling in the differentiation and maintenance of specialized lineages of self-reactive T cells.
Figure 4: Hypothetical mechanisms of TGFβ1-mediated control of effector T cells.
Figure 5: Positive and negative regulation of peripheral T-cell differentiation by TGFβ1.

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Acknowledgements

This work was supported by a Sandler Foundation award and by grants from the National Institutes of Health, USA. A.Y.R. is an investigator with the Howard Hughes Medical Institute.

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  1. Department of Immunology, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    Yuri P Rubtsov & Alexander Y Rudensky

  2. Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, 98195, Washington, USA

    Alexander Y Rudensky

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Glossary

NKT cell

(Natural killer T cell). A T cell that expresses both natural killer (NK)-cell receptors and an αβT-cell receptor (αβTCR). In mice, these cells were first identified by their expression of the alloantigen NK1.1 (also known as NKRP1C). Some mouse NKT cells express an invariant TCR that uses the Vα14 variable region of the TCR α-chain and recognizes CD1d-associated antigen. NKT cells are characterized by cytolytic activity and rapid production of cytokines, including interferon-γ and interleukin-4, and they might regulate the function of other T cells.

α-GalCer–CD1d tetramers

Tetrameric forms of CD1d molecules bound to α-galactosylceramide (α-GalCer), which have sufficient affinity for the T-cell receptor of invariant natural killer T (iNKT) cells to allow the detection of iNKT cells by flow cytometry.

Tonic 'tickling'

A term used for a low-affinity engagement of the T-cell receptor, which occurs in response to self antigens and is thought to be important for the maintenance and homeostatic proliferation of T cells.

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Rubtsov, Y., Rudensky, A. TGFβ signalling in control of T-cell-mediated self-reactivity. Nat Rev Immunol 7, 443–453 (2007). https://doi.org/10.1038/nri2095

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