TGF‐β in the Immune Response


Transforming growth factor‐β (TGF‐β) is a highly evolutionally conserved cytokine that is critical for embryogenesis, cancer and matrix formation and immune responses. Three distinct isoforms, TGF‐β1, 2 and 3, are found in mammals. TGF‐β is secreted by immune and nonhematopoietic cells and acts on virtually all cell types through ubiquitously expressed receptors, which transduce the TGF‐β signal through canonical Smad‐dependent pathway and noncanonical Smad‐independent pathways. In particular, TGF‐β plays a crucial role in immune tolerance and maintains immune homeostasis by inhibiting proliferation, differentiation, activation and effector function of immune cells. On the other side of the coin, TGF‐β can display proinflammatory properties, depending on the context. The more complete understanding of the various functions of TGF‐β in the immune system, especially in tolerance, will enable us to design more specific and effective therapies for immune disorders.

Key Concepts

  • TGF‐β is a multifunctional cytokine that mainly suppresses immune responses to maintain immune homeostasis.
  • TGF‐β signalling is transduced via not only its unique protein, Smad, but also via Smad‐independent pathways.
  • T cells are the major targets of TGF‐β in immune system and its activation/proliferation, apoptosis and differentiation are regulated by TGF‐β.
  • TGF‐β is a key mediator for the regulation of autoimmune diseases.

Keywords: TGF‐β; immune tolerance; autoimmune disease; helper T cell differentiation; regulatory T cell

Figure 1. TGF‐β signalling. Latent TGF‐β consists of TGF‐β, latent TGF‐β‐binding protein (LTBP) and latency‐associated protein (LAP), and requires activation in order to bind to its receptor. Bioactive TGF‐β binds TβRIIs, which are constitutively phosphorylated, and subsequently recruit and phosphorylate TβRIs. In the Smad‐dependent pathway, activated TβRs phosphorylate Smad2 and/or Smad3 and subsequently interact with Smad4 that enables Smad2/3 to translocate into the nucleus. Binding of the Smad complex to the Smad‐binding element (SBE) regulates target gene expression. In Smad‐independent pathways, mitogen‐activated protein kinases (MAPK), phosphatidylinositol‐3 kinase (PI3K)‐Akt‐mTOR, TNF receptor‐associated factor 6 (TRAF6)/TGF‐β‐activated kinase 1 (TAK1)‐MAP kinase kinases (MKKs)‐p38 MAPK and small GTPases can be activated downstream of TGF‐β/TβR interaction.
Figure 2. The role of TGF‐β in helper T cell differentiation. In the periphery, naïve CD4+ T cells differentiate into subpopulations of helper T cells upon activation. TGF‐β promotes differentiation of Treg, Th17 and Th9 cells, whereas the differentiation of Th1, Th2 and Th22 cells is inhibited by TGF‐β. The role of TGF‐β in Tfh cell differentiation is still unknown. TGF‐β appears to be involved in the tTreg differentiation in the thymus.


Allen JB, Manthey CL, Hand AR, et al. (1990) Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta. Journal of Experimental Medicine 171 (1): 231–247.

Armitage RJ, Macduff BM, Spriggs MK and Fanslow WC (1993) Human B cell proliferation and Ig secretion induced by recombinant CD40 ligand are modulated by soluble cytokines. Journal of Immunology 150 (9): 3671–3680.

Arsura M, Wu M and Sonenshein GE (1996) TGF beta 1 inhibits NF‐kappa B/Rel activity inducing apoptosis of B cells: transcriptional activation of I kappa B alpha. Immunity 5 (1): 31–40.

Basu R, O'Quinn DB, Silberger DJ, et al. (2012) Th22 cells are an important source of IL‐22 for host protection against enteropathogenic bacteria. Immunity 37 (6): 1061–1075.

Blanchette F, Rivard N, Rudd P, et al. (2001) Cross‐talk between the p42/p44 MAP kinase and Smad pathways in transforming growth factor beta 1‐induced furin gene transactivation. Journal of Biological Chemistry 276 (36): 33986–33994.

Brown CB, Boyer AS, Runyan RB and Barnett JV (1999) Requirement of type III TGF‐beta receptor for endocardial cell transformation in the heart. Science 283 (5410): 2080–2082.

Capocasale RJ, Lamb RJ, Vonderheid EC, et al. (1995) Reduced surface expression of transforming growth factor beta receptor type II in mitogen‐activated T cells from Sezary patients. Proceedings of the National Academy of Sciences of the United States of America 92 (12): 5501–5505.

Cazac BB and Roes J (2000) TGF‐beta receptor controls B cell responsiveness and induction of IgA in vivo. Immunity 13 (4): 443–451.

Chen CH, Seguin‐Devaux C, Burke NA, et al. (2003a) Transforming growth factor beta blocks Tec kinase phosphorylation, Ca2+ influx, and NFATc translocation causing inhibition of T cell differentiation. Journal of Experimental Medicine 197 (12): 1689–1699.

Chen W, Jin W, Hardegen N, et al. (2003b) Conversion of peripheral CD4+ CD25− naive T cells to CD4+ CD25+ regulatory T cells by TGF‐beta induction of transcription factor Foxp3. Journal of Experimental Medicine 198 (12): 1875–1886.

Cheroutre H, Lambolez F and Mucida D (2011) The light and dark sides of intestinal intraepithelial lymphocytes. Nature Reviews Immunology 11 (7): 445–456.

Duhen T, Geiger R, Jarrossay D, et al. (2009) Production of interleukin 22 but not interleukin 17 by a subset of human skin‐homing memory T cells. Nature Immunology 10 (8): 857–863.

Eyerich S, Eyerich K, Pennino D, et al. (2009) Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. Journal of Clinical Investigation 119 (12): 3573–3585.

Fox FE, Ford HC, Douglas R, et al. (1993) Evidence that TGF‐beta can inhibit human T‐lymphocyte proliferation through paracrine and autocrine mechanisms. Cellular Immunology 150 (1): 45–58.

Friese MA, Wischhusen J, Wick W, et al. (2004) RNA interference targeting transforming growth factor‐beta enhances NKG2D‐mediated antiglioma immune response, inhibits glioma cell migration and invasiveness, and abrogates tumorigenicity in vivo. Cancer Research 64 (20): 7596–7603.

Ghoreschi K, Laurence A, Yang XP, et al. (2010) Generation of pathogenic T(H)17 cells in the absence of TGF‐beta signalling. Nature 467 (7318): 967–971.

Gorelik L and Flavell RA (2000) Abrogation of TGFbeta signaling in T cells leads to spontaneous T cell differentiation and autoimmune disease. Immunity 12 (2): 171–181.

Gorelik L and Flavell RA (2001) Immune‐mediated eradication of tumors through the blockade of transforming growth factor‐beta signaling in T cells. Nature Medicine 7 (10): 1118–1122.

Gorham JD, Guler ML, Fenoglio D, et al. (1998) Low dose TGF‐beta attenuates IL‐12 responsiveness in murine Th cells. Journal of Immunology 161 (4): 1664–1670.

Ichiyama K, Sekiya T, Inoue N, et al. (2011) Transcription factor Smad‐independent T helper 17 cell induction by transforming‐growth factor‐beta is mediated by suppression of eomesodermin. Immunity 34 (5): 741–754.

Johns LD, Flanders KC, Ranges GE and Sriram S (1991) Successful treatment of experimental allergic encephalomyelitis with transforming growth factor‐beta 1. Journal of Immunology 147 (6): 1792–1796.

Kehrl JH, Wakefield LM, Roberts AB, et al. (1986) Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. Journal of Experimental Medicine 163 (5): 1037–1050.

Konkel JE, Jin W, Abbatiello B, et al. (2014) Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. Proceedings of the National Academy of Sciences of the United States of America 111 (4): E465–E473.

Kuwahara M, Yamashita M, Shinoda K, et al. (2012) The transcription factor Sox4 is a downstream target of signaling by the cytokine TGF‐beta and suppresses T(H)2 differentiation. Nature Immunology 13 (8): 778–786.

Lee Y, Awasthi A, Yosef N, et al. (2012) Induction and molecular signature of pathogenic TH17 cells. Nature Immunology 13 (10): 991–999.

Letterio JJ, Geiser AG, Kulkarni AB, et al. (1996) Autoimmunity associated with TGF‐beta1‐deficiency in mice is dependent on MHC class II antigen expression. Journal of Clinical Investigation 98 (9): 2109–2119.

Lin JT, Martin SL, Xia L and Gorham JD (2005) TGF‐beta 1 uses distinct mechanisms to inhibit IFN‐gamma expression in CD4+ T cells at priming and at recall: differential involvement of Stat4 and T‐bet. Journal of Immunology 174 (10): 5950–5958.

Liu Y, Zhang P, Li J, et al. (2008) A critical function for TGF‐beta signaling in the development of natural CD4+ CD25+ Foxp3+ regulatory T cells. Nature Immunology 9 (6): 632–640.

Lu L, Wang J, Zhang F, et al. (2010) Role of SMAD and non‐SMAD signals in the development of Th17 and regulatory T cells. Journal of Immunology 184 (8): 4295–4306.

Ludviksson BR, Seegers D, Resnick AS and Strober W (2000) The effect of TGF‐beta1 on immune responses of naive versus memory CD4+ Th1/Th2 T cells. European Journal of Immunology 30 (7): 2101–2111.

Mangan PR, Harrington LE, O'Quinn DB, et al. (2006) Transforming growth factor‐beta induces development of the T(H)17 lineage. Nature 441 (7090): 231–234.

Marie JC, Liggitt D and Rudensky AY (2006) Cellular mechanisms of fatal early‐onset autoimmunity in mice with the T cell‐specific targeting of transforming growth factor‐beta receptor. Immunity 25 (3): 441–454.

McCarron MJ and Marie JC (2014) TGF‐beta prevents T follicular helper cell accumulation and B cell autoreactivity. Journal of Clinical Investigation 124 (10): 4375–4386.

McGeachy MJ, Bak‐Jensen KS, Chen Y, et al. (2007) TGF‐beta and IL‐6 drive the production of IL‐17 and IL‐10 by T cells and restrain T(H)‐17 cell‐mediated pathology. Nature Immunology 8 (12): 1390–1397.

Racke MK, Dhib‐Jalbut S, Cannella B, et al. (1991) Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor‐beta 1. Journal of Immunology 146 (9): 3012–3017.

Rao PE, Petrone AL and Ponath PD (2005) Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF‐{beta}. Journal of Immunology 174 (3): 1446–1455.

Sakaguchi S, Vignali DA, Rudensky AY, et al. (2013) The plasticity and stability of regulatory T cells. Nature Reviews Immunology 13 (6): 461–467.

Schlenner SM, Weigmann B, Ruan Q, et al. (2012) Smad3 binding to the foxp3 enhancer is dispensable for the development of regulatory T cells with the exception of the gut. Journal of Experimental Medicine 209 (9): 1529–1535.

Schmitt N, Liu Y, Bentebibel SE, et al. (2014) The cytokine TGF‐beta co‐opts signaling via STAT3‐STAT4 to promote the differentiation of human TFH cells. Nature Immunology 15 (9): 856–865.

Shull MM, Ormsby I, Kier AB, et al. (1992) Targeted disruption of the mouse transforming growth factor‐beta 1 gene results in multifocal inflammatory disease. Nature 359 (6397): 693–699.

Stritesky GL, Jameson SC and Hogquist KA (2012) Selection of self‐reactive T cells in the thymus. Annual Review of Immunology 30: 95–114.

Takimoto T, Wakabayashi Y, Sekiya T, et al. (2010) Smad2 and Smad3 are redundantly essential for the TGF‐beta‐mediated regulation of regulatory T plasticity and Th1 development. Journal of Immunology 185 (2): 842–855.

Tamiya T, Ichiyama K, Kotani H, et al. (2013) Smad2/3 and IRF4 play a cooperative role in IL‐9‐producing T cell induction. Journal of Immunology 191 (5): 2360–2371.

Thorbecke GJ, Shah R, Leu CH, et al. (1992) Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proceedings of the National Academy of Sciences of the United States of America 89 (16): 7375–7379.

Tone Y, Furuuchi K, Kojima Y, et al. (2008) Smad3 and NFAT cooperate to induce Foxp3 expression through its enhancer. Nature Immunology 9 (2): 194–202.

van Vlasselaer P, Punnonen J and de Vries JE (1992) Transforming growth factor‐beta directs IgA switching in human B cells. Journal of Immunology 148 (7): 2062–2067.

Wahl SM, Allen JB, Costa GL, et al. (1993) Reversal of acute and chronic synovial inflammation by anti‐transforming growth factor beta. Journal of Experimental Medicine 177 (1): 225–230.

Wahl SM (1994) Transforming growth factor beta: the good, the bad, and the ugly. Journal of Experimental Medicine 180 (5): 1587–1590.

Wang A, Pan D, Lee YH, et al. (2013) Cutting edge: Smad2 and Smad4 regulate TGF‐beta‐mediated Il9 gene expression via EZH2 displacement. Journal of Immunology 191 (10): 4908–4912.

Zheng Y, Josefowicz S, Chaudhry A, et al. (2010) Role of conserved non‐coding DNA elements in the Foxp3 gene in regulatory T‐cell fate. Nature 463 (7282): 808–812.

Zhou X, Kong N, Zou H, et al. (2011) Therapeutic potential of TGF‐beta‐induced CD4(+) Foxp3(+) regulatory T cells in autoimmune diseases. Autoimmunity 44 (1): 43–50.

Zhu S, Pan W, Shi P, et al. (2010) Modulation of experimental autoimmune encephalomyelitis through TRAF3‐mediated suppression of interleukin 17 receptor signaling. Journal of Experimental Medicine 207 (12): 2647–2662.

Further Reading

Chen W and Wahl SM (2002) TGF‐beta: receptors, signalling pathways and autoimmunity. Current Directions in Autoimmunity 5: 62–91.

Kuklina EM (2013) Molecular mechanisms of T‐cell anergy. Biochemistry (Mosc) 78 (2): 144–156.

Li MO, Wan YY, Sanjabi S, Robertson AK and Flavell RA (2006) Transforming growth factor‐beta regulation of immune responses. Annual Review of Immunology 24: 99–146.

Mantel PY and Schmidt‐Weber CB (2011) Transforming growth factor‐beta: recent advances on its role in immune tolerance. Methods in Molecular Biology 677: 303–338.

Oh SA and Li MO (2013) TGF‐beta: guardian of T cell function. Journal of Immunology 191 (8): 3973–3979.

Ohkura N, Kitagawa Y and Sakaguchi S (2013) Development and maintenance of regulatory T cells. Immunity 38 (3): 414–423.

Schuster N and Krieglstein K (2002) Mechanisms of TGF‐beta‐mediated apoptosis. Cell and Tissue Research 307 (1): 1–14.

Tirado‐Rodriguez B, Ortega E, Segura‐Medina P and Huerta‐Yepez S (2014) TGF‐beta: an important mediator of allergic disease and a molecule with dual activity in cancer development. Journal of Immunology Research. Article ID: 318481, 15 pages..

Zhang YE (2009) Non‐Smad pathways in TGF‐beta signalling. Cell Research 19 (1): 128–139.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Nakatsukasa, Hiroko, Tu, Eric, Chia, Cheryl Pei Zhi, and Chen, WanJun(Sep 2015) TGF‐β in the Immune Response. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0021546]