- Shi, Y. & Massague, J. Mechanisms of TGF-β signaling from cell membrane to the nucleus. Cell 113, 685–700 (2003).
Article CAS Google Scholar
- Siegel, P. M. & Massague, J. Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nature Rev. Cancer 3, 807–821 (2003).
Article CAS Google Scholar
- Kehrl, J. H. et al. Production of transforming growth factor β by human T lymphocytes and its potential role in the regulation of T cell growth. J. Exp. Med. 163, 1037–1050 (1986). This is the first study to implicate an important role for TGFβ1 produced by activated T cells in limiting their proliferation.
Article CAS Google Scholar
- Li, M. O., Wan, Y. Y., Sanjabi, S., Robertson, A. K. & Flavell, R. A. Transforming growth factor-β regulation of immune responses. Annu. Rev. Immunol. 24, 99–144 (2006).
Article CAS Google Scholar
- Veldhoen, M. & Stockinger, B. TGFβ1, a 'Jack of all trades': the link with pro-inflammatory IL-17-producing T cells. Trends Immunol. 27, 358–361 (2006).
Article CAS Google Scholar
- Li, M. O., Sanjabi, S. & Flavell, R. A. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25, 455–471 (2006). This study and reference 7 reveal a critical role for TGFβ1 signalling in T cells in preventing fatal early onset autoimmune lesions affecting multiple organs.
Article CAS Google Scholar
- Marie, J. C., Liggitt, D. & Rudensky A. Y. Cellular mechanisms of fatal early-onset autoimmunity in mice with the T cell-specific targeting of transforming growth factor-β receptor. Immunity 25, 441–454 (2006).
Article CAS Google Scholar
- Fantini, M. C. et al. TGF-β induces a regulatory phenotype in CD45+CD25− T cells through FoxP3 induction and down-regulation of Smad7. J. Immunol. 172, 5149–5153 (2004).
Article CAS Google Scholar
- Marie, J. C., Letterio, J. J., Gavin, M. & Rudensky A. Y. TGF-β1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 1061–1067 (2005).
Article CAS Google Scholar
- Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).
Article CAS Google Scholar
- Fontenot, J. D. & Rudensky, A. Y. Molecular aspects of regulatory T cell development. Semin. Immunol. 16, 73–80 (2004).
Article CAS Google Scholar
- Govinden, R. & Bhoola, K. D. Genealogy, expression, and cellular function of transforming growth factor-β. Pharmacol. Ther. 98, 257–265 (2003).
Article CAS Google Scholar
- Letterio, J. J. & Roberts, A. B. Regulation of immune responses by TGF-β. Annu. Rev. Immunol. 16, 137–161 (1998).
Article CAS Google Scholar
- Lagneaux, L., Delforge, A., Dorval, C., Bron, D. & Stryckmans, P. Excessive production of transforming growth factor-β by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production. Blood 82, 2379–2385 (1993).
CAS PubMed Google Scholar
- Filer, A., Pitzalis, C. & Buckley C. D. Targeting the stromal microenvironment in chronic inflammation. Curr. Opin. Pharmacol. 6, 394–400 (2006).
Article Google Scholar
- Kim, S. J. et al. Autoinduction of transforming growth factor β1 is mediated by the AP-1 complex. Mol. Cell. Biol. 10, 1492–1497 (1990).
Article CAS Google Scholar
- Lee, K. Y. et al. NF-κB and activator protein 1 response elements and the role of histone modifications in IL-1β-induced TGF-β1 gene transcription. J. Immunol. 176, 603–615 (2006).
Article CAS Google Scholar
- Kim, S. J. et al. Post-transcriptional regulation of the human transforming growth factor-β1 gene. J. Biol. Chem. 267, 13702–13707 (1992).
CAS PubMed Google Scholar
- Annes, J. P., Munger, J. S. & Rifkin, D. B. Making sense of latent TGFβ activation. J. Cell. Sci. 116, 217–224 (2003).
Article CAS Google Scholar
- Nunes, I., Shapiro, R. L. & Rifkin, D. B. Characterization of latent TGF-β activation by murine peritoneal macrophages. J. Immunol. 155, 1450–1459 (1995).
CAS PubMed Google Scholar
- Crawford, S. E. et al. Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 93, 1159–1170 (1998).
Article CAS Google Scholar
- Munger, J. S. et al. The integrin αvβ6 binds and activates latent TGFβ1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96, 319–328 (1999).
Article CAS Google Scholar
- Annes, J. P., Chen, Y., Munger, J. S. & Rifkin, D. B. Integrin αVβ6-mediated activation of latent TGF-β requires the latent TGF-β binding protein-1. J. Cell Biol. 165, 723–734 (2004).
Article CAS Google Scholar
- Chaudhry, S. S. et al. Fibrillin-1 regulates the bioavailability of TGFβ1. J. Cell. Biol. 176, 355–367 (2007).
Article CAS Google Scholar
- Zhang, X. et al. Recovery from experimental allergic encephalomyelitis is TGF-β dependent and associated with increases in CD4+LAP+ and CD4+CD25+ T cells. Int. Immunol. 18, 495–503 (2006).
Article CAS Google Scholar
- Gandhi, R., Anderson, D. E. & Weiner, H. L. Immature human dendritic cells express latency-associated peptide and inhibit T cell activation in a TGF-β-dependent manner. J. Immunol. 178, 4017–4021 (2007).
Article CAS Google Scholar
- Mitti, P. R. et al. The crystal structure of TGF-β3 and comparison to TGF-β2: implications for receptor binding. Protein Sci. 5, 1261–1271 (1996).
Article Google Scholar
- Massague, J. TGF-β signal transduction. Ann. Rev. Biochem. 67, 753–791 (1998).
Article CAS Google Scholar
- Massague, J. How cells read TGF-β signals. Nature Rev. Mol. Cell. Biol. 1, 169–178 (2000).
Article CAS Google Scholar
- Huse, M. et al. The TGF-β receptor activation process: an inhibitor- to substrate-binding switch. Mol. Cell 8, 671–682 (2001).
Article CAS Google Scholar
- Massague, J. & Chen, Y.-G. Controlling TGF-β signaling. Genes Dev. 14, 627–644 (2000).
CAS PubMed Google Scholar
- Tsukazaki, T., Chiang, T. A., Davison, A. F., Attisano, L. & Wrana, J. T. SARA, a FYVE domain protein that recruits Smad2 to the TGF-β receptor. Cell 95, 779–791 (1998).
Article CAS Google Scholar
- Inman, G. J., Nicolas, F. J. & Hill, C. S. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-β receptor activity. Mol. Cell 10, 283–294 (2002).
Article CAS Google Scholar
- Xu, L., Chen, Y.-G. & Massague, J. Smad2 nuclear import function masked by SARA and unmasked by TGF-β dependent phosphorylation. Nature Cell. Biol. 2, 559–562 (2000).
Article CAS Google Scholar
- Xu, L., Kang, Y., Col, S. & Massague, J. Smad2 nucleocytoplasmic shuttling by nucleoporins CAN/Nup214 and Nup153 feeds TGF-β signaling complexes in the cytoplasm and nucleus. Mol. Cell 10, 271–282 (2002).
Article CAS Google Scholar
- Suzuki, C. et al. Smurf1 regulates the inhibitory activity of Smad7 by targeting Smad7 to the plasma membrane. J. Biol. Chem. 277, 39919–39925 (2002).
Article CAS Google Scholar
- Tajima, Y. et al. Chromosomal region maintenance 1 (CRM1)-dependent nuclear export of Smad ubiquitin regulatory factor 1 (Smurf1) is essential for negative regulation of transforming growth factor-β signaling by Smad7. J. Biol. Chem. 278, 10716–10721 (2003).
Article CAS Google Scholar
- Di Guglielmo, G. M., Le Roy, C., Davidson, A. F. & Wrana, J. L. Distinct endocytic pathways regulate TGF- β receptor signaling and turnover. Nature Cell Biol. 5, 410–421 (2003).
Article CAS Google Scholar
- Bhowmick, N. A. et al. Transforming growth factor-β1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. Mol. Biol. Cell 12, 27–36 (2001).
Article CAS Google Scholar
- Yu, L., Hebert, M. C. & Zhang, Y. E. TGF-β receptor-activated p38 MAP kinase mediated Smad-independent TGF-β responses. EMBO J. 21, 3749–3759 (2002).
Article CAS Google Scholar
- Itoh, S. et al. Elucidation of Smad requirement in transforming growth factor-β type I receptor-induced responses. J. Biol. Chem. 278, 3751–3761 (2003).
Article CAS Google Scholar
- Shull, M. M. et al. Targeted disruption of the mouse transforming growth factor-β1 gene results in multifocal inflammatory disease. Nature 359, 693–699 (1992).
Article CAS Google Scholar
- Nikolich-Zugich, J. Phenotypic and functional stages in the intrathymic development of αβT cells. Immunol. Today 12, 65–70 (1991).
Article Google Scholar
- Suda, T. & Zlotnik, A. IL-7 maintains the T cell precusor potential of CD3−CD4−CD8− thymocytes. J. Immunol. 146, 3068–3073 (1991).
CAS PubMed Google Scholar
- Suda, T. & Zlotnik, A. In vitro induction of CD8 expression on thymic pre-T cells. II. Characterization of CD3−CD4−CD8α+ cells generated in vitro by culturing CD25+CD3−CD4−CD8− thymocytes with T cell growth factor-β and tumor necrosis factor-α. J. Immunol. 149, 71–76 (1992).
CAS PubMed Google Scholar
- Plum, J., De Smedt, M., Leclercq, G. & Vandekerckhove, B. Influence of TGF-β on murine thymocyte development in fetal thymus organ culture. J. Immunol. 154, 5789–5798 (1995).
CAS PubMed Google Scholar
- Mossalayi, M. D. et al. Early human thymocyte proliferation is regulated by an externally controlled autocrine transforming growth factor-β1 mechanism. Blood 85, 3594–35601 (1995).
CAS PubMed Google Scholar
- Takahama, Y., Letterio, J. J., Suzuki, H., Farr, A. G. & Singer, A. Early progression of thymocytes along the CD4/CD8 developmental pathway is regulated by a subset of thymic epithelial cells expressing transforming growth factor β. J. Exp. Med. 179, 1495–1506 (1994).
Article CAS Google Scholar
- Bendelac, A., Savage, P. B. & Teyton, L. The biology of NKT cells. Annu. Rev. Immunol. 25, 297–336 (2007).
Article CAS Google Scholar
- Benlagha, K., Wei, D. G., Veiga, J., Teyton, L. & Bendelac, A. Characterization of the early stages of thymic NKT cell development. J. Exp. Med. 202, 485–492 (2005).
Article CAS Google Scholar
- Wolfraim, L. A., Walz, T. M., James, Z., Fernandez, T. & Letterio, J. J. p21Cip1 and p27Kip1 act in synergy to alter the sensitivity of naïve T cells to TGF-β-mediated G1 arrest through modulation of IL-2 responsiveness. J. Immunol. 173, 3093–3102 (2004).
Article CAS Google Scholar
- Ruegemer, J. J. et al. Regulatory effects of transforming growth factor-β on IL-2- and IL-4-dependent T cell-cycle progression. J. Immunol. 144, 1767–1776 (1994).
Google Scholar
- Genestier, L., Kasibhatla, S., Brunner, T. & Green, D. R. Transforming growth factor β1 inhibits Fas ligand expression and subsequent activation-induced cell death in T cells via downregulation of c-Myc. J. Exp. Med. 189, 231–239 (1999).
Article CAS Google Scholar
- Nelson, B. H., Martyak, T. P., Thompson, L. J., Moon, J. J. & Wang, T. Uncoupling of promitogenic and antiapoptotic functions of IL-2 by Smad-dependent TGF-β signaling. J. Immunol. 170, 5563–5570 (2003).
Article CAS Google Scholar
- McKarns, S. C. & Schwartz, R. H. Distinct effects of TGF-β1 on CD4+ and CD8+ T cell survival, division, and IL-2 production: a role for T cell intrinsic Smad3. J. Immunol. 174, 2071–2083 (2005).
Article CAS Google Scholar
- Fahlen, L. et al. T cells that cannot respond to TGF-β escape control by CD4+CD25+ regulatory T cells. J. Exp. Med. 201, 737–746 (2005).
Article CAS Google Scholar
- Gorelik, L. & Flavell, R. A. Abrogation of TGFβ signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12, 171–181 (2000).
- Lucas, P. J., Kim, S-J., Melby, S. J. & Gress, R. E. Disruption of T cell homeostasis in mice expressing a T cell-specific dominant negative transforming growth factor βII receptor. J. Exp. Med. 191, 1187–1196 (2000). References 57 and 58 were the first to indicate an important cell-autonomous role for TGFβ1 signalling in T cells by expressing a dominant-negative form of TGFβRII under the control of a T-cell-specific promoter.
Article CAS Google Scholar
- Gorelik, L., Constant, S. & Flavell, R. A. Mechanism of transforming growth factor-β-induced inhibition of T helper type 1 differentiation. J. Exp. Med. 195, 1499–1505 (2002).
Article CAS Google Scholar
- Fontenot, J. D. & Rudensky, A. Y. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nature Immunol. 6, 331–337 (2005).
Article CAS Google Scholar
- Fontenot, J. D. et al. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity 22, 329–341 (2005).
Article CAS Google Scholar
- Khattri, R., Cox, T., Yasayko, S. A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nature Immunol. 4, 337–342 (2003).
Article CAS Google Scholar
- Fontenot, J. D., Gavin, M. A. & Rudensky, A. Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nature Immunol. 4, 330–336 (2003).
Article CAS Google Scholar
- Yamagiwa, S., Gray, J. D., Hashimoto, S. & Horwitz, D. A. A role for TGF-β in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J. Immunol. 166, 7282–7289 (2001). The authors of this paper demonstrate that in the presence of high doses of TGFβ1 and stimulation in vitro , conventional T cells acquire the ability to suppress the responses of untreated T cells.
Article CAS Google Scholar
- Chen, W. et al. Conversion of peripheral CD4+CD25− naive T cells to CD4+CD25+ regulatory T cells by TGF-β induction of transcription factor Foxp3. J. Exp. Med. 198, 1875–1886 (2003). This is the first report providing evidence that TGFβ1 facilitates the induction of FOXP3 expression in CD4+CD25 − cells.
Article CAS Google Scholar
- Davidson, T. S., DiPaolo, R. J., Andersson, J. & Shevach, E. M. IL-2 is essential for TGFβ-mediated induction of Foxp3+ T regulatory cells. J. Immunol. 178, 4022–4026 (2007).
Article CAS Google Scholar
- Zheng, S. G., Wang, J., Wang, P., Gray, J. D. & Horwitz, D. A. IL-2 is essential for TGF-β to convert naive CD4+CD25− cells to CD25+Foxp3+ regulatory T cells and for expansion of these cells. J. Immunol. 178, 2018–2027 (2007).
Article CAS Google Scholar
- Li, O. M., Wan, Y. Y. & Flavell, R. A. T cell-produced transforming growth factor-β1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 3 May 2007 (doi:10.1016/j.immuni.2007.03.014).
Article CAS Google Scholar
- Thomas, D. A. & Massague, J. TGF-β directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell 8, 369–380 (2005). This study shows that TGFβ1 signalling in CD8+ T cells inhibits activity against tumour cells, indicating a possible mechanism of tumour evasion from the immune response.
Article CAS Google Scholar
- Roncarolo, M. G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).
Article CAS Google Scholar
- Faria, A. M. & Weiner, H. L. Oral tolerance. Immunol. Rev. 206, 232–259 (2005).
Article CAS Google Scholar
- Bettelli, E., Oukka, M. & Kuchroo, V. K. TH-17 cells in the circle of immunity and autoimmunity. Nature Immunol. 8, 345–350 (2007).
Article CAS Google Scholar
- Weaver, C. T., Hatton R. D., Mangan, P. R. & Harrington, L. E. IL-17 family cytokines and the expanding diversity of effector T cell lineages. Annu. Rev. Immunol. 25, 821–852 (2007).
Article CAS Google Scholar
- Veldhoen, M., Hocking, R. J., Atkins, C. J, Locksley, R. M. & Stockinger, B. TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24, 179–189 (2006).
Article CAS Google Scholar
- Bettelli, E. et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441, 235–238 (2006).
Article CAS Google Scholar
- Harrington, L. E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nature Immunol. 6, 1123–1132 (2005). References 74–76 describe an important role for TGFβ1 signalling in the differentiation of IL-17-producing CD4+ T cells.
Article CAS Google Scholar
- Ivanov, I. I. et al. The orphan nuclear receptor RORγt directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell 126, 1121–1133 (2006). This study reveals a key role for the transcription factor RORγt in TGFβ1- and IL-6-dependent differentiation of T H 17 cells.
Article CAS Google Scholar
- Gavin, M. A. et al. Foxp3-dependent programme of regulatory T-cell differentiation. Nature 445, 771–775 (2007).
Article CAS Google Scholar
- Williams, L. M. & Rudensky, A. Y. Maintenance of the Foxp3-dependent developmental program in mature regulatory T cells requires continued expression of Foxp3. Nature Immunol. 8, 277–284 (2007).
Article CAS Google Scholar