Top

Published in:

01-10-2017 | Review

The role of TGF-beta signaling in dendritic cell tolerance

Authors: Grace E. Esebanmen, William H. R. Langridge

Published in: Immunologic Research | Issue 5/2017

Abstract

Transforming growth factor beta (TGF-β) is a pleiotropic cytokine present in vertebrate and invertebrate organisms that functions in numerous physiological and pathological processes. TGF-β impacts all the cells of the immune system, and of the three known TGF-β isoforms, TGF-β1 is the predominant isoform expressed in immune cells. TGF-β1 is known to play a pivotal role in the function of all immune cells especially in the regulation of T cell development and in the induction of immunological tolerance in dendritic cells (DCs). Based on the importance of DCs in regulation of the innate and adaptive arms of the immune system, in this review we explore the regulatory functions of TGF-β required for establishment and maintenance of DC-mediated immune tolerance.

Massague J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6(1):597–641. doi:10.1146/annurev.cb.06.110190.003121.CrossRefPubMed

Clark DA, Coker R. Molecules in focus transforming growth factor-beta (TGF-β). Int J Biochem Cell Biol. 1998;30(3):293–8. doi:10.1016/S1357-2725(97)00128-3.CrossRefPubMed

Li MO, Wan YY, Sanjabi S, Robertson A-KL, Flavell RA. Transforming growth factor-β regulation of immune responses. Annu Rev Immunol. 2006;24(1):99–146. doi:10.1146/annurev.immunol.24.021605.090737.CrossRefPubMed

Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor β in human disease. N Engl J Med. 2000;342(18):1350–8. doi:10.1056/NEJM200005043421807.CrossRefPubMed

Herpin A, Lelong C, Favrel P. Transforming growth factor-β-related proteins: an ancestral and widespread superfamily of cytokines in metazoans. Developmental & Comparative Immunology. 2004;28(5):461–85. doi:10.1016/j.dci.2003.09.007.CrossRef

Letterio JJ, Roberts AB. Regulation of immune responses by TGF-β. Annu Rev Immunol. 1998;16(1):137–61. doi:10.1146/annurev.immunol.16.1.137.CrossRefPubMed

Guerder S, Joncker N, Mahiddine K, Serre L. Dendritic cells in tolerance and autoimmune diabetes. Curr Opin Immunol. 2013;25(6):670–5. doi:10.1016/j.coi.2013.10.004.CrossRefPubMed

Li MO, Sanjabi S, Flavell RA. Transforming growth factor-β controls development, homeostasis, and tolerance of T cells by regulatory T cell-dependent and -independent mechanisms. Immunity. 2006;25(3):455–71. doi:10.1016/j.immuni.2006.07.011.CrossRefPubMed

Mu D, Cambier S, Fjellbirkeland L, Baron JL, Munger JS, Kawakatsu H, et al. The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-β1. J Cell Biol. 2002;157(3):493–507. doi:10.1083/jcb.200109100.CrossRefPubMedPubMedCentral

10.

Melton AC, Bailey-Bucktrout SL, Travis MA, Fife BT, Bluestone JA, Sheppard D. Expression of alphavbeta8 integrin on dendritic cells regulates Th17 cell development and experimental autoimmune encephalomyelitis in mice. J Clin Invest. 2010;120(12):4436–44. doi:10.1172/JCI43786.CrossRefPubMedPubMedCentral

11.

Prud’homme GJ, Piccirillo CA. The inhibitory effects of transforming growth factor-beta-1 (TGF-β1) in autoimmune diseases. J Autoimmun. 2000;14(1):23–42. doi:10.1006/jaut.1999.0339.CrossRefPubMed

12.

Aoki CA, Borchers AT, Li M, Flavell RA, Bowlus CL, Ansari AA, et al. Transforming growth factor β (TGF-β) and autoimmunity. Autoimmun Rev. 2005;4(7):450–9. doi:10.1016/j.autrev.2005.03.006.CrossRefPubMed

13.

Kriegel M, Li M, Sanjabi S, Wan Y, Flavell R. Transforming growth factor-β: recent advances on its role in immune tolerance. Curr Rheumatol Rep. 2006;8(2):138–44. doi:10.1007/s11926-006-0054-y.CrossRefPubMed

14.

Worthington JJ, Fenton TM, Czajkowska BI, Klementowicz JE, Travis MA. Regulation of TGFβ in the immune system: an emerging role for integrins and dendritic cells. Immunobiology. 2012;217(12):1259–65. doi:10.1016/j.imbio.2012.06.009.CrossRefPubMedPubMedCentral

15.

Travis MA, Sheppard D. TGF-β activation and function in immunity. Annu Rev Immunol. 2014;32:51–82. doi:10.1146/annurev-immunol-032713-120257.CrossRefPubMed

16.

Annes JP, Munger JS, Rifkin DB. Making sense of latent TGFβ activation. J Cell Sci. 2003;116(2):217.CrossRefPubMed

17.

Li MO, Flavell RA. Contextual regulation of inflammation: a duet by transforming growth factor-β and interleukin-10. Immunity. 2008;28(4):468–76. doi:10.1016/j.immuni.2008.03.003.CrossRefPubMed

18.

Annes J, Munger J, Rifkin D. Making sense of latent TGFbeta activation. J Cell Sci. 2003;116(Pt 2):217–24.CrossRefPubMed

19.

Wipff P-J, Hinz B. Integrins and the activation of latent transforming growth factor β1—an intimate relationship. Eur J Cell Biol. 2008;87(8–9):601–15. doi:10.1016/j.ejcb.2008.01.012.CrossRefPubMed

20.

Massagué J. TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012;13(10):616–30. doi:10.1038/nrm3434.CrossRefPubMedPubMedCentral

21.

Massagué J, Gomis RR. The logic of TGFβ signaling. FEBS Lett. 2006;580(12):2811–20. doi:10.1016/j.febslet.2006.04.033.CrossRefPubMed

22.

Huminiecki L, Goldovsky L, Freilich S, Moustakas A, Ouzounis C, Heldin C-H. Emergence, development and diversification of the TGF-β signalling pathway within the animal kingdom. BMC Evol Biol. 2009;9:28. doi:10.1186/1471-2148-9-28.CrossRefPubMedPubMedCentral

23.

Moustakas A, Heldin CH. The regulation of TGFbeta signal transduction. Development. 2009;136(22):3699–714. doi:10.1242/dev.030338.CrossRefPubMed

24.

Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-[beta] family signalling. Nature. 2003;425(6958):577–84.CrossRefPubMed

25.

Schridde A, Bain CC, Mayer JU, Montgomery J, Pollet E, Denecke B, et al. Tissue-specific differentiation of colonic macrophages requires TGF[beta] receptor-mediated signaling. Mucosal Immunol. 2017; doi:10.1038/mi.2016.142.

26.

Chen W, Jin W, Hardegen N, Lei K-J, Li L, Marinos N, 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. 2003;198(12):1875–86. doi:10.1084/jem.20030152.CrossRefPubMedPubMedCentral

27.

Nakamura K, Kitani A, Fuss I, Pedersen A, Harada N, Nawata H, et al. TGF-β1 plays an important role in the mechanism of CD4+CD25+ regulatory T cell activity in both humans and mice. J Immunol. 2004;172(2):834.CrossRefPubMed

28.

Worthington John J, Kelly A, Smedley C, Bauché D, Campbell S, Marie Julien C, et al. Integrin αvβ8-mediated TGF-β activation by effector regulatory T cells is essential for suppression of T-cell-mediated inflammation. Immunity. 2015;42(5):903–15. doi:10.1016/j.immuni.2015.04.012.CrossRefPubMedPubMedCentral

29.

Massagué J. TGFβ in cancer. Cell. 2008;134(2):215–30. doi:10.1016/j.cell.2008.07.001.CrossRefPubMedPubMedCentral

30.

Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, et al. Tumor cells convert immature myeloid dendritic cells into TGF-β–secreting cells inducing CD4(+)CD25(+) regulatory T cell proliferation. J Exp Med. 2005;202(7):919–29. doi:10.1084/jem.20050463.CrossRefPubMedPubMedCentral

31.

Park BV, Freeman ZT, Ghasemzadeh A, Chattergoon MA, Rutebemberwa A, Steigner J, et al. TGF-β1-mediated Smad3 enhances PD-1 expression on antigen-specific T cells in cancer. Cancer discovery. 2016;6(12):1366–81. doi:10.1158/2159-8290.CD-15-1347.CrossRefPubMedPubMedCentral

32.

Ding G, Niu J, Liu Y. Dental pulp stem cells suppress the proliferation of lymphocytes via transforming growth factor-β1. Hum Cell. 2015;28(2):81–90. doi:10.1007/s13577-014-0106-y.CrossRefPubMed

33.

Kwack KH, Lee JM, Park SH, Lee HW. Human dental pulp stem cells suppress alloantigen-induced immunity by stimulating T cells to release transforming growth factor beta. J Endod. 2017;43(1):100–8. doi:10.1016/j.joen.2016.09.005.CrossRefPubMed

34.

Coombes JL, Siddiqui KRR, Arancibia-Cárcamo CV, Hall J, Sun C-M, Belkaid Y, et al. A functionally specialized population of mucosal CD103(+) DCs induces Foxp3(+) regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism. J Exp Med. 2007;204(8):1757–64. doi:10.1084/jem.20070590.CrossRefPubMedPubMedCentral

35.

H-b M, Lin M-f, Cen H, Yu J, X-j M. TGF-β1 treated murine dendritic cells are maturation resistant and down-regulate Toll-like receptor 4 expression. Journal of Zhejiang University Science. 2004;5(10):1239–44. doi:10.1631/jzus.2004.1239.CrossRef

36.

Mou HB, Lin MF, Huang H, Cai Z. Transforming growth factor-β1 modulates lipopolysaccharide-induced cytokine/chemokine production and inhibits nuclear factor-κB, extracellular signal-regulated kinases and p38 activation in dendritic cells in mice. Transplant Proc. 2011;43(5):2049–52. doi:10.1016/j.transproceed.2011.02.054.CrossRefPubMed

37.

Nishimura SL, Sheppard D, Pytela R. Integrin alpha v beta 8. Interaction with vitronectin and functional divergence of the beta 8 cytoplasmic domain. J Biol Chem. 1994;269(46):28708–15.PubMed

38.

Evans R, Patzak I, Svensson L, De Filippo K, Jones K, McDowall A, et al. Integrins in immunity. J Cell Sci. 2009;122(2):215–25. doi:10.1242/jcs.019117.CrossRefPubMed

39.

Song K-H, Cho S-J, Song J-Y. αvβ1 integrin as a novel therapeutic target for tissue fibrosis. Annals of Translational Medicine. 2016;4(20):411. doi:10.21037/atm.2016.10.33.CrossRefPubMedPubMedCentral

40.

Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, et al. Loss of integrin α(v)β(8) on dendritic cells causes autoimmunity and colitis in mice. Nature. 2007;449(7160):361–5. doi:10.1038/nature06110.CrossRefPubMedPubMedCentral

41.

Aluwihare P, Mu Z, Zhao Z, Yu D, Weinreb P, Horan G, et al. Mice that lack activity of alphavbeta6- and alphavbeta8-integrins reproduce the abnormalities of Tgfb1- and Tgfb3-null mice. J Cell Sci. 2009;122:227–32.CrossRefPubMed

42.

Païdassi H, Acharya M, Zhang A, Mukhopadhyay S, Kwon M, Chow C, et al. Preferential expression of integrin αvβ8 promotes generation of regulatory T cells by mouse CD103+ dendritic cells. Gastroenterology. 2011;141(5):1813–20. doi:10.1053/j.gastro.2011.06.076.CrossRefPubMedPubMedCentral

43.

Worthington JJ, Czajkowska BI, Melton AC, Travis MA. Intestinal dendritic cells specialize to activate transforming growth factor-β and induce Foxp3(+) regulatory T cells via integrin αvβ8. Gastroenterology. 2011;141(5):1802–12. doi:10.1053/j.gastro.2011.06.057.CrossRefPubMedPubMedCentral

44.

Fenton TM, Kelly A, Shuttleworth EE, Smedley C, Atakilit A, Powrie F, et al. Inflammatory cues enhance TGFβ activation by distinct subsets of human intestinal dendritic cells via integrin αvβ8. Mucosal Immunol. 2017;10(3):624–34. doi:10.1038/mi.2016.94.CrossRefPubMed

45.

van Duivenvoorde LM, van Mierlo GJD, Boonman ZFHM, Toes REM. Dendritic cells: vehicles for tolerance induction and prevention of autoimmune diseases. Immunobiology. 2006;211(6–8):627–32. doi:10.1016/j.imbio.2006.05.014.CrossRefPubMed

46.

Benson RA, Brewer JM, Platt AM. Mechanisms of autoimmunity in human diseases: a critical review of current dogma. Curr Opin Rheumatol. 2014;26(2):197–203. doi:10.1097/bor.0000000000000037.CrossRefPubMed

47.

Ohnmacht C, Pullner A, King SBS, Drexler I, Meier S, Brocker T, et al. Constitutive ablation of dendritic cells breaks self-tolerance of CD4 T cells and results in spontaneous fatal autoimmunity. J Exp Med. 2009;206(3):549–59. doi:10.1084/jem.20082394.CrossRefPubMedPubMedCentral

48.

Schinnerling K, Soto L, García-González P, Catalán D, Aguillón JC. Skewing dendritic cell differentiation towards a tolerogenic state for recovery of tolerance in rheumatoid arthritis. Autoimmun Rev. 2015;14(6):517–27. doi:10.1016/j.autrev.2015.01.014.CrossRefPubMed

49.

Van Brussel I, Lee WP, Rombouts M, Nuyts AH, Heylen M, De Winter BY, et al. Tolerogenic dendritic cell vaccines to treat autoimmune diseases: can the unattainable dream turn into reality? Autoimmun Rev. 2014;13(2):138–50. doi:10.1016/j.autrev.2013.09.008.CrossRefPubMed

50.

Randolph GJ, Ochando J, Partida-Sanchez S. Migration of dendritic cell subsets and their precursors. Annu Rev Immunol. 2008;26:293–316. doi:10.1146/annurev.immunol.26.021607.090254.CrossRefPubMed

51.

Kaliński P, Hilkens CMU, Wierenga EA, Kapsenberg ML. T-cell priming by type-1and type-2 polarized dendritic cells: the concept of a third signal. Immunol Today. 1999;20(12):561–7. doi:10.1016/S0167-5699(99)01547-9.CrossRefPubMed

52.

García-González P, Ubilla-Olguín G, Catalán D, Schinnerling K, Aguillón JC. Tolerogenic dendritic cells for reprogramming of lymphocyte responses in autoimmune diseases. Autoimmun Rev. 2016;15(11):1071–80. doi:10.1016/j.autrev.2016.07.032.CrossRefPubMed

53.

Ten Brinke A, Hilkens CMU, Cools N, Geissler EK, Hutchinson JA, Lombardi G, et al. Clinical use of tolerogenic dendritic cells—harmonization approach in European collaborative effort. Mediat Inflamm. 2015;2015:471719. doi:10.1155/2015/471719.

54.

Hilkens CMU, Isaacs JD, Thomson AW. Development of dendritic cell-based immunotherapy for autoimmunity. Int Rev Immunol. 2010;29(2):156–83. doi:10.3109/08830180903281193.CrossRefPubMed

55.

Broggi A, Zanoni I, Granucci F. Migratory conventional dendritic cells in the induction of peripheral T cell tolerance. J Leukoc Biol. 2013;94(5):903–11. doi:10.1189/jlb.0413222.CrossRefPubMed

56.

Gordon JR, Ma Y, Churchman L, Gordon SA, Dawicki W. Regulatory dendritic cells for immunotherapy in immunologic diseases. Front Immunol. 2014;5:7. doi:10.3389/fimmu.2014.00007.CrossRefPubMedPubMedCentral

57.

Mukhopadhaya A, Hanafusa T, Jarchum I, Chen Y-G, Iwai Y, Serreze DV, et al. Selective delivery of β cell antigen to dendritic cells in vivo leads to deletion and tolerance of autoreactive CD8(+) T cells in NOD mice. Proc Natl Acad Sci U S A. 2008;105(17):6374–9. doi:10.1073/pnas.0802644105.CrossRefPubMedPubMedCentral

58.

Mahnke K, Schmitt E, Bonifaz L, Enk AH, Jonuleit H. Immature, but not inactive: the tolerogenic function of immature dendritic cells. Immunol Cell Biol. 2002;80(5):477–83.CrossRefPubMed

59.

Jauregui-Amezaga A, Cabezón R, Ramírez-Morros A, España C, Rimola J, Bru C, et al. Intraperitoneal administration of autologous tolerogenic dendritic cells for refractory Crohn’s disease: a phase I study. Journal of Crohn's and Colitis. 2015;9(12):1071.CrossRef

60.

Giannoukakis N, Phillips B, Finegold D, Harnaha J, Trucco M. Phase I (safety) study of autologous tolerogenic dendritic cells in type 1 diabetic patients. Diabetes Care. 2011;34(9):2026–32. doi:10.2337/dc11-0472.CrossRefPubMedPubMedCentral

61.

Benham H, Nel HJ, Law SC, Mehdi AM, Street S, Ramnoruth N, et al. Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype–positive rheumatoid arthritis patients. Sci Transl Med. 2015;7(290):290ra87.CrossRefPubMed

62.

Ronger-Savle S, Valladeau J, Claudy A, Schmitt D, Peguet-Navarro J, Dezutter-Dambuyant C, et al. TGFβ inhibits CD1d expression on dendritic cells. J Investig Dermatol. 2005;124(1):116–8. doi:10.1111/j.0022-202X.2004.23315.x.CrossRefPubMed

63.

Gerlini G, Hefti HP, Kleinhans M, Nickoloff BJ, Burg G, Nestle FO. CD1d is expressed on dermal dendritic cells and monocyte-derived dendritic cells. J Investig Dermatol. 2001;117(3):576–82. doi:10.1046/j.0022-202x.2001.01458.x.CrossRefPubMed

64.

Rosat J-P, Grant EP, Beckman EM, Dascher CC, Sieling PA, Frederique D, et al. CD1-restricted microbial lipid antigen-specific recognition found in the CD8+ αβ T cell pool. J Immunol. 1999;162(1):366.PubMed

65.

Abediankenari S, Ghasemi M, Kim Y-J. Human leukocyte antigen-G expression on dendritic cells induced by transforming growth factor-β1 and CD4(+) T cells proliferation. Iran Biomed J. 2011;15(1–2):1–5.PubMedPubMedCentral

66.

Olavio RB, Marina S, Loredana M, Roberta R. HLA-G and inflammatory diseases. Inflammation & Allergy - Drug Targets (Discontinued). 2008;7(2):67–74. doi:10.2174/187152808785107615.CrossRef

67.

Adnan E, Matsumoto T, Ishizaki J, Onishi S, Suemori K, Yasukawa M, et al. Human tolerogenic dendritic cells generated with protein kinase C inhibitor are optimal for functional regulatory T cell induction—a comparative study. Clin Immunol. 2016;173:96–108. doi:10.1016/j.clim.2016.09.007.CrossRefPubMed

68.

Denniston AK, Kottoor SH, Khan I, Oswal K, Williams GP, Abbott J, et al. Endogenous cortisol and TGF-β in human aqueous humor contribute to ocular immune privilege by regulating dendritic cell function. J Immunol. 2010;186(1):305.CrossRefPubMed

69.

Issazadeh S, Mustafa M, Ljungdahl Å, Höjeberg B, Dagerlind Å, Elde R, et al. Interferon γ, interleukin 4 and transforming growth factor β in experimental autoimmune encephalomyelitis in lewis rats: dynamics of cellular mrna expression in the central nervous system and lymphoid cells. J Neurosci Res. 1995;40(5):579–90. doi:10.1002/jnr.490400503.CrossRefPubMed

70.

Laouar Y, Town T, Jeng D, Tran E, Wan Y, Kuchroo VK, et al. TGF-β signaling in dendritic cells is a prerequisite for the control of autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2008;105(31):10865–70. doi:10.1073/pnas.0805058105.CrossRefPubMedPubMedCentral

71.

Speck S, Lim J, Shelake S, Matka M, Stoddard J, Farr A, et al. TGF-β signaling initiated in dendritic cells instructs suppressive effects on Th17 differentiation at the site of neuroinflammation. PLoS One. 2014;9(7):e102390. doi:10.1371/journal.pone.0102390.CrossRefPubMedPubMedCentral

72.

DiPaolo RJ, Brinster C, Davidson TS, Andersson J, Glass D, Shevach EM. Autoantigen-specific TGFβ-induced Foxp3+ regulatory T cells prevent autoimmunity by inhibiting dendritic cells from activating autoreactive T cells. J Immunol. 2007;179(7):4685.CrossRefPubMed

73.

Darrasse-Jèze G, Deroubaix S, Mouquet H, Victora GD, Eisenreich T, Yao K-H, et al. Feedback control of regulatory T cell homeostasis by dendritic cells in vivo. J Exp Med. 2009;206(9):1853–62. doi:10.1084/jem.20090746.CrossRefPubMedPubMedCentral

74.

Ramalingam R, Larmonier CB, Thurston RD, Midura-Kiela MT, Zheng SG, Ghishan FK, et al. Dendritic cell-specific disruption of TGFβ receptor II leads to altered regulatory T-cell phenotype and spontaneous multi-organ autoimmunity. Journal of immunology (Baltimore, Md : 1950). 2012;189(8):3878–93. doi:10.4049/jimmunol.1201029.CrossRef

75.

Boomershine CS, Chamberlain A, Kendall P, Afshar-Sharif AR, Huang H, Washington MK, et al. Autoimmune pancreatitis results from loss of TGFβ signalling in S100A4-positive dendritic cells. Gut. 2009;58(9):1267–74. doi:10.1136/gut.2008.170779.CrossRefPubMedPubMedCentral

76.

Boucard-Jourdin M, Kugler D, Endale Ahanda M-L, This S, De Calisto J, Zhang A, et al. β8 integrin expression and activation of TGF-β by intestinal dendritic cells is determined by both tissue microenvironment and cell lineage. Journal of immunology (Baltimore, Md : 1950). 2016;197(5):1968–78. doi:10.4049/jimmunol.1600244.CrossRef

Title: The role of TGF-beta signaling in dendritic cell tolerance
Authors: Grace E. Esebanmen
William H. R. Langridge
Publication date: 01-10-2017
Publisher: Springer US
Published in: Immunologic Research / Issue 5/2017
Print ISSN: 0257-277X
Electronic ISSN: 1559-0755
DOI: https://doi.org/10.1007/s12026-017-8944-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

The role of TGF-beta signaling in dendritic cell tolerance

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2017

Potential therapeutic use of IL-37: a key suppressor of innate immunity and allergic immune responses mediated by mast cells

Platelet factor 4 increases bone marrow B cell development and differentiation

Interleukin-10 production and T cell-suppressive capacity in B cell subsets from atherosclerotic apoE −/− mice

Growth arrest-specific protein 7 regulates the murine M1 alveolar macrophage polarization

Plasma alpha-L-fucosidase activity in chronic inflammation and autoimmune disorders in a pediatric cohort of hospitalized patients

Signaling interactions predicted by the Tritope model of the TCR