Skip to main content

Role of TGF-β in Immune Suppression and Inflammation

  • Chapter
  • First Online:
Innate Immune Regulation and Cancer Immunotherapy
  • 1806 Accesses

Abstract

Transforming growth factor-β (TGF-β) a family of cytokines ubiquitously produced and responded to by almost all cells, plays critical roles in the regulation of immune responses in the physiological as well as pathological settings. While traditionally considered an immunologically “non-specific” regulatory cytokine influencing the phenotype and function of innate and adaptive immune cells, TGF-β has been recently uncovered to “specifically” reprogram naïve CD4+ T cells to certain T cell lineages. In this regard, TGF-β is found to serve as a “master switch” in programming naïve CD4+ T lymphocytes into either Foxp3+ regulatory T cells (Treg cells) or Th17 pro-inflammatory effector cells in the context of T cell receptor engagement and respective cytokine milieu. With continuous expansion of our knowledge of TGF-β regulation of immune responses, it is imperative to understand the common and individual molecular mechanisms by which TGF-β signals in immune cells. It is also important to explore the pathways to apply the basic concept to the development of immunotherapy in experimental, and ultimately clinical, settings. In this chapter, we will highlight key findings on how TGF-β influences the innate and adaptive immune systems, with focus on recent progress concerning TGF-β regulation of T cell differentiation/function, and discuss the link between TGF-β regulation of immune responses and pathogenesis of autoimmunity, chronic inflammation and cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Allen JB, Manthey CL, Hand AR, Ohura K, Ellingsworth L, Wahl SM (1990) Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta. J Exp Med 171:231–247

    Article  PubMed  CAS  Google Scholar 

  • Andersson J, Tran DQ, Pesu M, Davidson TS, Ramsey H, O’Shea JJ, Shevach EM (2008) CD4+ FoxP3+ regulatory T cells confer infectious tolerance in a TGF-beta-dependent manner. J Exp Med 205:1975–1981

    Article  PubMed  CAS  Google Scholar 

  • Apostolou I, von Boehmer H (2004) In vivo instruction of suppressor commitment in naive T cells. J Exp Med 199:1401–1408

    Article  PubMed  CAS  Google Scholar 

  • Bellone G, Aste-Amezaga M, Trinchieri G, Rodeck U (1995) Regulation of NK cell functions by TGF-beta 1. J Immunol 155:1066–1073

    PubMed  CAS  Google Scholar 

  • Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK (2006) Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441:235–238

    Article  PubMed  CAS  Google Scholar 

  • Bogdan C, Paik J, Vodovotz Y, Nathan C (1992) Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. J Biol Chem 267:23301–23308

    PubMed  CAS  Google Scholar 

  • Bommireddy R, Engle SJ, Ormsby I, Boivin GP, Babcock GF, Doetschman T (2004) Elimination of both CD4+ and CD8+ T cells but not B cells eliminates inflammation and prolongs the survival of TGF-beta1-deficient mice. Cell Immunol 232:96–104

    Article  PubMed  CAS  Google Scholar 

  • Bommireddy R, Pathak LJ, Martin J, Ormsby I, Engle SJ, Boivin GP, Babcock GF, Eriksson AU, Singh RR, Doetschman T (2006) Self-antigen recognition by TGF-beta1-deficient T cells causes their activation and systemic inflammation. Lab Invest 86:1008–1019

    Article  PubMed  CAS  Google Scholar 

  • Borkowski TA, Letterio JJ, Farr AG, Udey MC (1996) A role for endogenous transforming growth factor beta 1 in Langerhans cell biology: the skin of transforming growth factor beta 1 null mice is devoid of epidermal Langerhans cells. J Exp Med 184:2417–2422

    Article  PubMed  CAS  Google Scholar 

  • Brabletz T, Pfeuffer I, Schorr E, Siebelt F, Wirth T, Serfling E (1993) Transforming growth factor beta and cyclosporin A inhibit the inducible activity of the interleukin-2 gene in T cells through a noncanonical octamer-binding site. Mol Cell Biol 13:1155–1162

    PubMed  CAS  Google Scholar 

  • Castriconi R, Cantoni C, Della Chiesa M, Vitale M, Marcenaro E, Conte R, Biassoni R, Bottino C, Moretta L, Moretta A (2003) Transforming growth factor beta 1 inhibits expression of NKp30 and NKG2D receptors: consequences for the NK-mediated killing of dendritic cells. Proc Natl Acad Sci USA 100:4120–4125

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Chatenoud L, Bluestone JA (2007) CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol 7:622–632

    Article  PubMed  CAS  Google Scholar 

  • Chen W, Frank ME, Jin W, Wahl SM (2001a) TGF-beta released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14:715–725

    Article  PubMed  CAS  Google Scholar 

  • Chen W, Jin W, Tian H, Sicurello P, Frank M, Orenstein JM, Wahl SM (2001b) Requirement for transforming growth factor beta1 in controlling T cell apoptosis. J Exp Med 194:439–453

    Article  PubMed  CAS  Google Scholar 

  • Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM (2003) Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 198:1875–1886

    Article  PubMed  CAS  Google Scholar 

  • Dennler S, Goumans MJ, ten Dijke P (2002) Transforming growth factor beta signal transduction. J Leukoc Biol 71:731–740

    PubMed  CAS  Google Scholar 

  • Derynck R, Zhang YE (2003) Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 425:577–584

    Article  PubMed  CAS  Google Scholar 

  • Doisne JM, Bartholin L, Yan KP, Garcia CN, Duarte N, Le Luduec JB, Vincent D, Cyprian F, Horvat B, Martel S et al (2009) iNKT cell development is orchestrated by different branches of TGF-beta signaling. J Exp Med 206:1365–1378

    Article  PubMed  CAS  Google Scholar 

  • Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101:890–898

    Article  PubMed  CAS  Google Scholar 

  • Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF (2004) Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol 172:5149–5153

    PubMed  CAS  Google Scholar 

  • Faunce DE, Terajewicz A, Stein-Streilein J (2004) Cutting edge: in vitro-generated tolerogenic APC induce CD8+ T regulatory cells that can suppress ongoing experimental autoimmune encephalomyelitis. J Immunol 172:1991–1995

    PubMed  CAS  Google Scholar 

  • Fiorentino DF, Bond MW, Mosmann TR (1989) Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170:2081–2095

    Article  PubMed  CAS  Google Scholar 

  • Geissmann F, Revy P, Regnault A, Lepelletier Y, Dy M, Brousse N, Amigorena S, Hermine O, Durandy A (1999) TGF-beta 1 prevents the noncognate maturation of human dendritic Langerhans cells. J Immunol 162:4567–4575

    PubMed  CAS  Google Scholar 

  • Gil-Guerrero L, Dotor J, Huibregtse IL, Casares N, Lopez-Vazquez AB, Rudilla F, Riezu-Boj JI, Lopez-Sagaseta J, Hermida J, Van Deventer S et al (2008) In vitro and in vivo down-regulation of regulatory T cell activity with a peptide inhibitor of TGF-beta1. J Immunol 181:126–135

    PubMed  CAS  Google Scholar 

  • Hahm KB, Im YH, Parks TW, Park SH, Markowitz S, Jung HY, Green J, Kim SJ (2001) Loss of transforming growth factor beta signalling in the intestine contributes to tissue injury in inflammatory bowel disease. Gut 49:190–198

    Article  PubMed  CAS  Google Scholar 

  • Jakowlew SB (2006) Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev 25:435–457

    Article  PubMed  CAS  Google Scholar 

  • Johns LD, Sriram S (1993) Experimental allergic encephalomyelitis: neutralizing antibody to TGF beta 1 enhances the clinical severity of the disease. J Neuroimmunol 47:1–7

    Article  PubMed  CAS  Google Scholar 

  • Kee BL, Rivera RR, Murre C (2001) Id3 inhibits B lymphocyte progenitor growth and survival in response to TGF-beta. Nat Immunol 2:242–247

    Article  PubMed  CAS  Google Scholar 

  • Kehrl JH, Roberts AB, Wakefield LM, Jakowlew S, Sporn MB, Fauci AS (1986a) Transforming growth factor beta is an important immunomodulatory protein for human B lymphocytes. J Immunol 137:3855–3860

    PubMed  CAS  Google Scholar 

  • Kehrl JH, Wakefield LM, Roberts AB, Jakowlew S, Alvarez-Mon M, Derynck R, Sporn MB, Fauci AS (1986b) Production of transforming growth factor beta by human T lymphocytes and its potential role in the regulation of T cell growth. J Exp Med 163:1037–1050

    Article  PubMed  CAS  Google Scholar 

  • Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H (2005) Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol 6:1219–1227

    Article  PubMed  CAS  Google Scholar 

  • Kulkarni AB, Huh CG, Becker D, Geiser A, Lyght M, Flanders KC, Roberts AB, Sporn MB, Ward JM, Karlsson S (1993) Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death. Proc Natl Acad Sci USA 90:770–774

    Article  PubMed  CAS  Google Scholar 

  • Lee JC, Lee KM, Kim DW, Heo DS (2004) Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol 172:7335–7340

    PubMed  CAS  Google Scholar 

  • Li MO, Sanjabi S, Flavell RA (2006) Transforming growth factor-beta controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity 25:455–471

    Article  PubMed  CAS  Google Scholar 

  • Li MO, Wan YY, Flavell RA (2007) T cell-produced transforming growth factor-beta1 controls T cell tolerance and regulates Th1- and Th17-cell differentiation. Immunity 26:579–591

    Article  PubMed  CAS  Google Scholar 

  • Liu Y, Zhang P, Li J, Kulkarni AB, Perruche S, Chen W (2008) A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Nat Immunol 9:632–640

    Article  PubMed  CAS  Google Scholar 

  • Marie JC, Liggitt D, 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 25:441–454

    Article  PubMed  CAS  Google Scholar 

  • McKarns SC, Schwartz RH, Kaminski NE (2004) Smad3 is essential for TGF-beta 1 to suppress IL-2 production and TCR-induced proliferation, but not IL-2-induced proliferation. J Immunol 172:4275–4284

    PubMed  CAS  Google Scholar 

  • Monteleone G, Kumberova A, Croft NM, McKenzie C, Steer HW, MacDonald TT (2001) Blocking Smad7 restores TGF-beta1 signaling in chronic inflammatory bowel disease. J Clin Invest 108:601–609

    PubMed  CAS  Google Scholar 

  • Morelli AE, Zahorchak AF, Larregina AT, Colvin BL, Logar AJ, Takayama T, Falo LD, Thomson AW (2001) Cytokine production by mouse myeloid dendritic cells in relation to differentiation and terminal maturation induced by lipopolysaccharide or CD40 ligation. Blood 98:1512–1523

    Article  PubMed  CAS  Google Scholar 

  • Nandan D, Reiner NE (1997) TGF-beta attenuates the class II transactivator and reveals an accessory pathway of IFN-gamma action. J Immunol 158:1095–1101

    PubMed  CAS  Google Scholar 

  • Nelson BH, Martyak TP, Thompson LJ, Moon JJ, Wang T (2003) Uncoupling of promitogenic and antiapoptotic functions of IL-2 by Smad-dependent TGF-beta signaling. J Immunol 170:5563–5570

    PubMed  CAS  Google Scholar 

  • Pasche B (2001) Role of transforming growth factor beta in cancer. J Cell Physiol 186:153–168

    Article  PubMed  CAS  Google Scholar 

  • Perruche S, Zhang P, Liu Y, Saas P, Bluestone JA, Chen W (2008) CD3-specific antibody-induced immune tolerance involves transforming growth factor-beta from phagocytes digesting apoptotic T cells. Nat Med 14:528–535

    Article  PubMed  CAS  Google Scholar 

  • Powrie F, Carlino J, Leach MW, Mauze S, Coffman RL (1996) A critical role for transforming growth factor-beta but not interleukin 4 in the suppression of T helper type 1-mediated colitis by CD45RB(low) CD4+ T cells. J Exp Med 183:2669–2674

    Article  PubMed  CAS  Google Scholar 

  • Qin S, Cobbold SP, Pope H, Elliott J, Kioussis D, Davies J, Waldmann H (1993) “Infectious” transplantation tolerance. Science 259:974–977

    Article  PubMed  CAS  Google Scholar 

  • Racke MK, Dhib-Jalbut S, Cannella B, Albert PS, Raine CS, McFarlin DE (1991) Prevention and treatment of chronic relapsing experimental allergic encephalomyelitis by transforming growth factor-beta 1. J Immunol 146:3012–3017

    PubMed  CAS  Google Scholar 

  • Robinson RT, French MA, Kitzmiller TJ, Gorham JD (2006) Restriction of the CD4+ T-cell receptor repertoire prevents immune pathology in TGF-beta1 knockout mice. Lab Invest 86:815–828

    PubMed  CAS  Google Scholar 

  • Roes J, Choi BK, Cazac BB (2003) Redirection of B cell responsiveness by transforming growth factor beta receptor. Proc Natl Acad Sci USA 100:7241–7246

    Article  PubMed  CAS  Google Scholar 

  • Rook AH, Kehrl JH, Wakefield LM, Roberts AB, Sporn MB, Burlington DB, Lane HC, Fauci AS (1986) Effects of transforming growth factor beta on the functions of natural killer cells: depressed cytolytic activity and blunting of interferon responsiveness. J Immunol 136:3916–3920

    PubMed  CAS  Google Scholar 

  • Sad S, Mosmann TR (1994) Single IL-2-secreting precursor CD4 T cell can develop into either Th1 or Th2 cytokine secretion phenotype. J Immunol 153:3514–3522

    PubMed  CAS  Google Scholar 

  • Shi Y, Massague J (2003) Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell 113:685–700

    Article  PubMed  CAS  Google Scholar 

  • Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693–699

    Article  PubMed  CAS  Google Scholar 

  • Strobl H, Bello-Fernandez C, Riedl E, Pickl WF, Majdic O, Lyman SD, Knapp W (1997) flt3 Ligand in cooperation with transforming growth factor-beta1 potentiates in vitro development of Langerhans-type dendritic cells and allows single-cell dendritic cell cluster formation under serum-free conditions. Blood 90:1425–1434

    PubMed  CAS  Google Scholar 

  • Takeuchi M, Alard P, Streilein JW (1998) TGF-beta promotes immune deviation by altering accessory signals of antigen-presenting cells. J Immunol 160:1589–1597

    PubMed  CAS  Google Scholar 

  • Thorbecke GJ, Shah R, Leu CH, Kuruvilla AP, Hardison AM, Palladino MA (1992) Involvement of endogenous tumor necrosis factor alpha and transforming growth factor beta during induction of collagen type II arthritis in mice. Proc Natl Acad Sci USA 89:7375–7379

    Article  PubMed  CAS  Google Scholar 

  • Tsunawaki S, Sporn M, Ding A, Nathan C (1988) Deactivation of macrophages by transforming growth factor-beta. Nature 334:260–262

    Article  PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B (2006a) TGF-beta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity 24:179–189

    Article  PubMed  CAS  Google Scholar 

  • Veldhoen M, Hocking RJ, Flavell RA, Stockinger B (2006b) Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol 7:1151–1156

    Article  PubMed  CAS  Google Scholar 

  • Vodovotz Y, Bogdan C, Paik J, Xie QW, Nathan C (1993) Mechanisms of suppression of macrophage nitric oxide release by transforming growth factor beta. J Exp Med 178:605–613

    Article  PubMed  CAS  Google Scholar 

  • Wolfraim LA, Walz TM, James Z, Fernandez T, Letterio JJ (2004) p21Cip1 and p27Kip1 Act in synergy to alter the sensitivity of naive T cells to TGF-beta-mediated G1 arrest through modulation of IL-2 responsiveness. J Immunol 173:3093–3102

    PubMed  CAS  Google Scholar 

  • Wrzesinski SH, Wan YY, Flavell RA (2007) Transforming growth factor-beta and the immune response: implications for anticancer therapy. Clin Cancer Res 13:5262–5270

    Article  PubMed  CAS  Google Scholar 

  • Yamagata T, Mathis D, Benoist C (2004) Self-reactivity in thymic double-positive cells commits cells to a CD8 alpha alpha lineage with characteristics of innate immune cells. Nat Immunol 5:597–605

    Article  PubMed  CAS  Google Scholar 

  • Zhou L, Lopes JE, Chong MM, Ivanov II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY et al (2008) TGF-beta-induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function. Nature 453:236–240

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Drs. T. Maruyama and P. Zhang, MIS, NIDCR, NIH for critically reading the manuscript. This research was supported by the intramural Research program of the NIH, National Institute for Dental and Craniofacial Research.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to WanJun Chen .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Konkel, J.E., Chen, W. (2012). Role of TGF-β in Immune Suppression and Inflammation. In: Wang, R. (eds) Innate Immune Regulation and Cancer Immunotherapy. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9914-6_16

Download citation

Publish with us

Policies and ethics