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Suppressing autoimmunity by TGF-β: not just through Treg cells

Cellular & Molecular Immunology volume 9, pages 371–372 (2012)Cite this article

Transforming growth factor-β (TGF-β) is a pleiotropic factor. It regulates many aspects of T-cell biology including thymocyte development, T cell differentiation and effector T cell function.1 Previous work has shown that the loss of TGF-β signaling in the T-cell lineage leads to severe lymphoproliferative autoimmunity.2,3 Until now, it has been unclear to what extent the autoimmunity observed in those mice is driven by TGF–unresponsive conventional T cells, as TGF- is also crucial for the maintenance and function of regulatory T cells (Treg). A recent study published in Nature Immunology revealed a novel role of TGF-β signaling in non-regulatory naive T cells. It was found that TGF-β controls lymphopenia-driven T-cell proliferation in neonatal mice, thereby preventing the development of autoimmunity.4

Zhang and Bevan made this discovery by comparing two animal models in which type II TGF-β receptor (TGF-βRII) was ablated in T cells at different developmental stages. In the previous study, researchers specifically deleted TGF-βRII using Cre recombinase driven by the promoter of CD4 (Tgfbr2f/f CD4-Cre). In this model system, TGF-βRII is deleted in T cells by the time they emerge from the thymus. As a result, these mice show severe autoimmunity and early mortality (3–5 weeks). The autoimmune phenotype observed in these mice cannot be rescued by transferring wild-type Treg cells or by reconstituting them with mixed bone marrow from wild-type and Tgfbr2f/f CD4-Cre mice.2,3 Together, these findings show that the onset of autoimmunity in the Tgfbr2f/f CD4-Cre model is at least partially due to the self-reactivity of TGF-β unresponsive conventional T cells. Zhang and Bevan studied a different TGF-βRII conditional deletion model, in which the expression of Cre is driven by the distal promoter of the kinase Lck (Tgfbr2f/f dLck-Cre). In this model, the T cell-specific deletion of TGF-βRII begins in mature T cells and is much slower. Although TGF-βRII is almost completely deleted in T cells in adult mice (7–9 weeks), the expression of TGF-βRII is unaffected in neonates (day 4). The delayed deletion of TGF-βRII led to a different phenotype: Tgfbr2f/f dLck-Cre showed no signs of autoimmune lesions and survived for up to a year.3,4

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Acknowledgements

We would like to thank Dr Claire Gordy for her thoughtful reading of this manuscript. The work in the authors' laboratory is supported by NIH grants AI73947, AI074754 and AI074944.

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  1. MX He, Box 3010, DUMC, Durham, NC 27710, USA. E-mail: mh106@duke.edu

  2. Or Dr YW He, Box 3010, DUMC, Durham, NC 27710, USA. E-mail: youwen.he@duke.edu

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  1. Department of Immunology, Duke University Medical Center, Durham, NC, USA

    Ming-Xiao He & You-Wen He

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He, MX., He, YW. Suppressing autoimmunity by TGF-β: not just through Treg cells. Cell Mol Immunol 9, 371–372 (2012). https://doi.org/10.1038/cmi.2012.24

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