Immunologic Research

, Volume 30, Issue 2, pp 155–170 | Cite as

Tolerogenic antigen-presenting cells

Regulation of the immune response by TGF-β-treated antigen-presenting cells
  • Michele M. Kosiewicz
  • Pascale Alard


Tolerogenic antigen-presenting cells (APCs) are attractive agents for the treatment of autoimmune and inflammatory diseases that are mediated, at least in part, by antigen-specific autoreactive T cells. Transforming growth factor-β (TGF-β)-treated antigen-presenting cells induce a very potent form of tolerance in mice. One unique feature of this simple and elegant method of tolerance induction is that it is equally potent in both primed and naïve mice, an important consideration for the development of a therapy that will be effective against an established disease. In this model, F4/80 peritoneal exudate cells (macrophages) cultured with antigen and TGF-β2 injected iv induce populations of regulatory T cells that mediate long-lasting antigen-specific tolerance in mice. The mechanisms that are involved in the induction of tolerance by TGF-β-treated APCs are very complex and require the interaction of a variety of cell types, as well as soluble and membrane-bound factors. In this review, we summarize the existing data and present new data concerning the induction and effector mechanisms associated with TGF-β-treated APC-induced tolerance. An understanding of these mechanisms will provide very important information for the design of effective strategies for the treatment of a variety of diseases that are mediated by pathogenic T cells.

Key Words

Tolerance Tolerogenic APC TGF-β Regulatory T cells FasL Autoimmune disease 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Asherson GL, Stone SH: Selective and specific inhibition of 24 hour skin reactions in the guinea-pig. 1. Immune deviation: description of the phenomenon and the effect of splenectomy. Immunology 1965;9:205–217.PubMedGoogle Scholar
  2. 2.
    Mosmann TR, Coffman RL: Heterogeneity of cytokine secretion patterns and functions of helper T cells. Adv Immunol 1989;46:111–147.PubMedCrossRefGoogle Scholar
  3. 3.
    Streilein JW, Niederkorn JY, Shadduck JA: Systemic immune unresponsiveness induced in adult mice by anterior chamber presentation of minor histocompatibility antigens. J Exp Med 1980;152:1121–1125.PubMedCrossRefGoogle Scholar
  4. 4.
    Streilein JW: Immune regulation and the eye: a dangerous compromise. FASEB J 1987;1:199–208.PubMedGoogle Scholar
  5. 5.
    Kosiewicz MM, Alard P, Streilein JW: Alterations in cytokine production following intraocular injection of soluble protein antigen: impairment in IFN-gamma and induction of TGF-beta and IL-4 production. J Immunol 1998;161:5382–5390.PubMedGoogle Scholar
  6. 6.
    Wilbanks GA, Streilein JW: Studies on the induction of anterior chamber-associated immune deviation (ACAID). 1. Evidence that an antigen-specific, ACAID-inducing, cell-associated signal exists in the peripheral blood. J Immunol 1991;146:2610–2617.PubMedGoogle Scholar
  7. 7.
    Wilbanks GA, Mammolenti M, Streilein JW: Studies on the induction of anterior chamber-associated immune deviation (ACAID). II. Eye-derived cells participate in generating blood-borne signals that induce ACAID. J Immunol 1991;146:3018–3024.PubMedGoogle Scholar
  8. 8.
    Streilein JW, Niederkorn JW: Characterization of the suppressor cell(s) responsible for Anterior Chamber Associated Immune Deviation (ACAID) induced in BALB/c mice by P815 cells. J Immunol 1985;134:1381–1387.PubMedGoogle Scholar
  9. 9.
    Wilbanks GA, Streilein JW: Characterization of suppressor cells in anterior chamber-associated immune deviation (ACAID) induced by soluble antigen. Evidence of two functionally and phenotypically distinct T-suppressor cell populations. Immunology 1990;71:383–389.PubMedGoogle Scholar
  10. 10.
    Kosiewicz MM, Okamoto S, Miki S, Ksander BR, Shimizu T, Streilein JW: Imposing deviant immunity on the presensitized state. J Immunol 1994;153:2962–2973.PubMedGoogle Scholar
  11. 11.
    Wilbanks GA, Mammolenti M, Streilein JW: Studies on the induction of anterior chamber-associated immune deviation (ACAID). III. Induction of ACAID depends upon intraocular transforming growth factor-beta. Eur J Immunol 1992;22:165–173.PubMedCrossRefGoogle Scholar
  12. 12.
    Cousins SW, McCabe MM, Danielpour D, Streilein JW: Identification of transforming growth factor- β as an immunosuppressive factor in aqueous humor. Invest Ophthalmol Vis Sci 1991;32:2201–2211.PubMedGoogle Scholar
  13. 13.
    Granstein RD, Staszewski R, Knisely TL, Zeira E, Nazareno R, Latina M, Albert DM: Aqueous humor contains transforming growth factor-β and a small (less than 3500 daltons) inhibitor of thymocyte proliferation. J Immunol 1990;144:3021–3027.PubMedGoogle Scholar
  14. 14.
    Taylor AW, Streilein JW, Cousins SW: Identification of a-melanocytes stimulating hormone as a potential immunosuppressive factor in aqueous humor. Curr Eye Res 1992;11:1199–1206.PubMedGoogle Scholar
  15. 15.
    Taylor AW, Streilein JW, Cousins SW: Immunoreactive vasoactive intestinal peptide contributes to the immuno-suppressive activity of normal aquous humor. J Immunol 1994;153:1080–1086.PubMedGoogle Scholar
  16. 16.
    Okano Y, Hara Y, Yao Y, Tano Y: In vitro-ACAID induction by culturing blood monocytes with transforming growth factor-beta, in Proceedings of the 6th International Symposium on the Immunology and Immunopathology of the Eye. Nussenblatt SM, Caspi RR, Gery I, eds. Elsevier Science B. V. Bethesda, MD, 1994, pp. 199–202.Google Scholar
  17. 17.
    Takeuchi M, Kosiewicz MM, Alard P, Streilein JW: On the mechanisms by which transforming growth factor-beta 2 alters antigen-presenting abilities of macrophages on T cell activation. Eur J Immunol 1997;27:1648–1656.PubMedCrossRefGoogle Scholar
  18. 18.
    Kosiewicz MM, Alard P, Clark SL: Mechanisms of tolerance induced by TGF-β-treated APC: CD4 regulatory T cells prevent the induction of the immune response possibly through a mechanism involving TGF β. Eur J Immunol 2004;34:1021–1030.PubMedCrossRefGoogle Scholar
  19. 19.
    Kosiewicz MM, Alard P, Liang S, Clark SL: Mechanisms of tolerance induced by TGFβ-treated APC: CD8 regulatory T cells inhibit the effector phase of the immune response in primed mice through a mechanism involving Fas ligand. Int Immunol 2004;16:697–706.PubMedCrossRefGoogle Scholar
  20. 20.
    Hara Y, Okamoto S, Rouse B, Streilein JW: Evidence that peritoneal exudate cells cultured with eye-derived fluids are the proximate antigen-presenting cells in immune deviation of the ocular type. J Immunol 1993;151:5162–5171.PubMedGoogle Scholar
  21. 21.
    Hara Y, Caspi RR, Wiggert B, Dorf M, Streilein JW: Analysis of an in vitro-generated signal that induces systemic immune deviation similar to that elicited by antigen injected into the anterior chamber of the eye. J Immunol 1992;149:1531–1538.PubMedGoogle Scholar
  22. 22.
    Sonoda K-H, Stein-Streilein J: CD1d on antigen-transporting APC and spelenic marginal zone B cells promotes NKT cell-dependent tolerance. Eur J Immunol 2002; 32:848–857.PubMedCrossRefGoogle Scholar
  23. 23.
    Kezuka T, Streilein JW: Evidence for multiple CD95-CD95 ligand interactions in anterior chamber-associated immune deviation induced by soluble protein antigen. Immunology 2000;99:451–457.PubMedCrossRefGoogle Scholar
  24. 24.
    D'orazio TJ, Niederkorn JY: A novel role for TGF-beta and IL-10 in the induction of immune privilege. J Immunol 1998;160:2089–2098.PubMedGoogle Scholar
  25. 25.
    Roncarolo MG, Leving MK: The role of differeet subsets of T regulatory cells in controlling autoimuity. Curr Opin Immunol 2000;12:676–683.PubMedCrossRefGoogle Scholar
  26. 26.
    Roncarolo MG, Bacchetta R, Bordignon C, Narula S Levings MK: Type 1 T regulatory cells. Immunol Rev 2001;182:68–79.PubMedCrossRefGoogle Scholar
  27. 27.
    Groux H, O'Garra A, Bigler M, Rouleau M, Antonenko S, de Vries JE, Roncarolo MG: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–742.PubMedCrossRefGoogle Scholar
  28. 28.
    Yehualaeshet T, O'Connor R, Green-Johnson J, Mai S, Silverstein R, Murphy-Ullrich JE, Khalil N: Activation of rat alveolar macrophage-derived latent transforming growth factor beta-1 by plasmin requires interaction with thrombospondin-1 and its cell surface receptor, CD36. Am J Pathol 1999;155:841–851.PubMedGoogle Scholar
  29. 29.
    Bendelac A, Rivera MN, Park SH, Roark JH: Mouse CD1-specific NK1 T cells: develoment, specificity, and function. Annu Rev Immunol 1997;15:535–562.PubMedCrossRefGoogle Scholar
  30. 30.
    Sonoda KH, Faunce DE, Taniguchi M, Exley M, Balk S, Stein-Streilein J: NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance. J Immunol 2001;166:42–50.PubMedGoogle Scholar
  31. 31.
    D'orazio TJ, Niederkorn JY: Splenic B cells are required for tolerogenic antigen presentation in the induction of anterior-associated immune deviation (ACAID). Immunology 1998;95:47–55.PubMedCrossRefGoogle Scholar
  32. 32.
    Carvalho LH, Sano G, Hafalla JC, Morrot A, Curotto de Lafaille MA, Zavala F: IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages. Nat Med 2002; 8:166–170.PubMedCrossRefGoogle Scholar
  33. 33.
    Li SP, Lee S-I, Wang Y, Domer JE: Candida albicans mannan-specific, delayed hypersensitivity down-regulatory CD8+ cells are genitically restricted effectors and their production requires CD4 and I-A expression. Int Arch Allergy Immunol 1996;109:334–343.PubMedCrossRefGoogle Scholar
  34. 34.
    Negoro T, Iinuma F, Watanabe M: Cellular induction mechanism of CD8+ suppressor T cells by DMBA and TPA: formation of CD4+ suppressor-inducer T cells. Cell Immunol 1996;167:216–223.PubMedCrossRefGoogle Scholar
  35. 35.
    Leishman AJ, Gapin L, Capone M, Palmer E, MacDonald HR, Kronenberg M, Cheroutre H: Precursors of functional MHC class I- or class II-restricted CD8alphaalpha(+) T cells are positively selected in the thymus by agonist selfpeptides. Immunity 2002;16:355–364.PubMedCrossRefGoogle Scholar
  36. 36.
    Kosiewicz MM, Streilein JW: Intraocular injection of class II-restricted peptide induces an unexpected population of CD8 regulatory cells. J Immunol 1996;157: 1905–1912.PubMedGoogle Scholar
  37. 37.
    Inobe J-I, Slavin AJ, Komagata Y, Chen Y, Liu L, Weiner HL: IL-4 is a differentiation factor for transforming growth factor-β secreting Th3 cells and oral administration of IL-4 enhances oral tolerance in experimental allergic encephalomyelitis. Eur J Immunol 1998;28: 2780–2790.PubMedCrossRefGoogle Scholar
  38. 38.
    King C, Mueller Hoenger R, Malo Cleary M, Murali-Krishna K, Ahmed R, King E, Sarvetnick N: Interleukin-4 acts at the locus of the antigen-presenting dendritic cell to counter-regulate cytotoxic CD8+ T-cell responses. Nat Med 2001; 7:206–214.PubMedCrossRefGoogle Scholar
  39. 39.
    Schuler T, Kammertoens T, Preiss S, Debs P, Noben-Trauth N, Blankenstein T: Generation of tumor-associated cytotoxic T lymphocytes requires interleukin 4 from CD8(+) T cells. J Exp Med 2001;194:1767–1775.PubMedCrossRefGoogle Scholar
  40. 40.
    Masli S, Turpie B, Hecker KH, Streilein, JW: Expression of thrombospondin in TGFβ-treated APCs and its relevance to their immune deviation-promoting properties. J Immunol 2002;168:2264–2273.PubMedGoogle Scholar
  41. 41.
    Crawford SE, Stellmach V, Murphy-Ullrich JE, Ribeiro, SMF, Lawler J, Hynes RO, et al.: Thrombospondin-1 is a major activator of TGF-β1 in vivo. Cell 1998;93: 1159–1170.PubMedCrossRefGoogle Scholar
  42. 42.
    Schultz-Cherry S, Chen H, Mosher DF, Misenheimer TM, Krutzsch HC, Roberts DD, Murphy-Ullrich JE: Regulation of transforming growth factor-β activation by discrete sequences of thrombospondin. J Biol Chem 1995;270:7304–7310.PubMedCrossRefGoogle Scholar
  43. 43.
    Yamagiwa S, Gray JD, Hashimoto S, Horwitz DA: A role for TGF-beta in the generation and expansion of CD4+CD25+ regulatory T cells from human peripheral blood. J Immunol 2001;166:7282–7289.PubMedGoogle Scholar
  44. 44.
    Kearney ER, Pape KA, Loh DY, Jenkins MK: Visualization of peptide-specific T cell immunity and peripheral tolerance induction in vivo. Immunity 1994; 1:327–339.PubMedCrossRefGoogle Scholar
  45. 45.
    Alard P, Clark SL, Kosiewicz MM: Deletion, but not anergy, is involved in TGF-β-treated antigen-presenting cell-induced tolerance. Int Immunol 2003;15:945–953.PubMedCrossRefGoogle Scholar
  46. 46.
    Okamoto S, Kosiewicz MM, Caspi RR, Streilein JW: ACAID as a potential therapy for established experimental autoimmune uveitis, in Advances in Ocular Immunology, Nussenblatt RB, Whitcup SM, Caspi RR, Gery I, eds. Elsevier Science B. V., Amsterdam, 1994, pp. 195–198.Google Scholar
  47. 47.
    Wong F, Karttunen J, Dumont L, Wen L, Visintin I, Pilip I, et al.: Identification of an MHC class I-restricted autoantigen in type I diabetes by screening an organ-specific cDNA library. Nat Med 1999;5:1026–1031.PubMedCrossRefGoogle Scholar
  48. 48.
    Jones CM, Callaghan JM, Gleeson PA, Mori Y, Masuda T, Toh BH: The parietal cell autoantigens recognized in neonatal thymectomy-induced murin gastritis are the alpha and beta subunits of the gastric proton pump. Gastroenterology 1991;101:287–294.PubMedGoogle Scholar
  49. 49.
    Kontani K, Taguchi O, Takahashi T: Involvement of the H+/K(+)-ATPase alpha subunit as a major antigenic protein in autoimmune gastritis induced by neonatal thymectomy in mice. Clin Exp Immunol 1992;89: 63–67.PubMedCrossRefGoogle Scholar
  50. 50.
    Nishio A, Hosono M, Watanabe Y, Sakai M, Okuma M, Masuda T: A conserved epitope on H+,K(+)-adenosine triphosphatase of parietal cells discerned by a murine gastritogenic T-cell clone. Gastroenterology 1994;107: 1408–1414.PubMedGoogle Scholar
  51. 51.
    Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M: Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995; 155:1151–1164.PubMedGoogle Scholar
  52. 52.
    Karpus WJ, Kennedy KJ, Smith WS, Miller SD: Inhibition of relapsing experimental autoimmune encephalomyelitis in SJL mice by feeding the immunodominant PLP139-151 peptide. J Neurosci Res 1996;45:410–423.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2004

Authors and Affiliations

  • Michele M. Kosiewicz
    • 1
  • Pascale Alard
    • 1
  1. 1.Health Sciences CenterUniversity of LouisvilleLouisville

Personalised recommendations