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TGF-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation

Nature Immunology volume 13, pages 667–673 (2012)Cite this article

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Abstract

T cell–specific deletion of the receptor for transforming growth factor-β (TGF-β) mediated by Cre recombinase expressed early in T cell development leads to early-onset lethal autoimmune disease that cannot be controlled by regulatory T cells. However, when we deleted that receptor through the use of Cre driven by a promoter that is active much later in T cell development, adult mice in which most peripheral CD4+ or CD8+ T cells lacked the receptor for TGF-β showed no signs of autoimmunity. Because of their enhanced responses to weak stimulation of the T cell antigen receptor, when transferred into lymphopenic recipients, naive TGF-β-unresponsive T cells underwent much more proliferation and differentiation into effector cells and induced lymphoproliferative disease. We propose that TGF-β signaling controls the self-reactivity of peripheral T cells but that in the absence of TGF-β signals, an added trigger such as lymphopenia is needed to drive overt autoimmune disease.

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Figure 1: Characterization of T cells in adult TGF-βRII-deficient mice.
Figure 2: Greatly enhanced lymphopenia-induced proliferation of TGF-βRII-deficient T cells in Rag1−/− mice.
Figure 3: TGF-βRII-deficient T cells induce lymphoproliferative disease in Rag1−/− recipient mice.
Figure 4: Considerably enhanced lymphopenia-induced proliferation of TGF-βRII-deficient T cells in sublethally irradiated B6 mice.
Figure 5: In vitro hyperproliferative response of TGF-βRII-deficient CD8+ T cells to weak stimulation.
Figure 6: In vitro hyperproliferative response of wild-type CD8+ T cells to weak stimulation in the absence of TGF-β.
Figure 7: TGF-βRII-deficient CD4+ T cells induce autoimmune disease in Rag1−/− mice, whereas TGF-βRII-deficient CD8+ T cells do so only in the presence of CD4+ T cells.

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Acknowledgements

We thank S. Karlsson (Lund University) for Tgfbr2f/f mice; P.J. Fink (University of Washington, Seattle) for mice with transgenic expression of Cre from the distal Lck promoter; A.G. Farr for help with histology, T. Bergsbaken for help with the immunofluorescence microscopy; and P.J. Fink for comments on the manuscript. Supported by US National Institutes of Health (AI19335) and the Howard Hughes Medical Institute.

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  1. Department of Immunology and the Howard Hughes Medical Institute, University of Washington, Seattle, Washington, USA

    Nu Zhang & Michael J Bevan

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  1. Nu Zhang
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N.Z. and M.J.B. designed experiments and wrote the paper, and N.Z. did the experiments.

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Correspondence to Michael J Bevan.

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Zhang, N., Bevan, M. TGF-β signaling to T cells inhibits autoimmunity during lymphopenia-driven proliferation. Nat Immunol 13, 667–673 (2012). https://doi.org/10.1038/ni.2319

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