Immunologic Research

, Volume 24, Issue 1, pp 69–77

Regulatory role of CD4+ T cells during the development of contact hypersensitivity responses

  • Anton V. Gorbachev
  • Robert L. Fairchild


Contac thypersensitivity (CHS) is a T cell-mediated immune response to cutaneous sensitization and subsequent challenge with haptens such as dinitrofluorobenzene and oxazolone. Many aspects concerning the development and regulation of CHS remain unknown. Using CHS as a model of T cell-mediated immune responses to antigens deposited in the skin we have studied the development and function of effector and regulatory T cell componenets of this response. These studies have revealed the effector role of hapten-specific CD8+ T cells in this response. In contrast, hapten-specific CD4+ T cells negatively regulate the magnitude and duration of the response. In this article we propose a model in which the CD4+ T cells during sensitization for CHS and discuss potential mechanisms that CD4+ T cells might utilize to mediate this regulation.

Key Words

Skin Contact hypersensitivity Langerhans cells T cells 


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  1. 1.
    Streilein JW: Skin-associated lymphoid tissues (SALT): Origins and functions. J Invest Derm 1983;80: 12s-16s.PubMedCrossRefGoogle Scholar
  2. 2.
    Dvorak HF, Galli SJ, Dvorak AM: Expression of cell-mediated hypersensitivity in vivo-recent advances. Int Rev Exp Pathol 1980;21: 119–194.PubMedGoogle Scholar
  3. 3.
    Cher DJ, Mosmann TR: Two types of murine helper T cell clone. II. Delayed-type hypersensitivity is mediated by TH 1 clone. J Immunol 1987;138:3688–3694.PubMedGoogle Scholar
  4. 4.
    Piguet PF, Grau GE, Hauser C, et al.: Tumor necrosis factor is a critical mediator in hapten-induced irritant and contact hypersensivity reactions. J Exp Med 1991: 173:673–679.PubMedCrossRefGoogle Scholar
  5. 5.
    Roupe G, Ridell B: The cellular infiltrate in contact sensitivity to picryl chloride in the mouse. Acta Dermato-Venereol 1979;59:191–195.Google Scholar
  6. 6.
    Kripke M, Munn C, Jeevan A, et al.: Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contatsensitization. J Immunol 1990; 145:2833–2838.PubMedGoogle Scholar
  7. 7.
    Macatonia SE, Knight SC, Edwards AJ, et al.: Localization of antigen on lymph node dendritic cells after exposure to the contact sensitizer fluorescein isothiocyanate. J Exp Med 1987;166: 1654–1667.PubMedCrossRefGoogle Scholar
  8. 8.
    Xu H, Dilulio NA, Fairchild RL: T cell populations primed by hapten sensitization in contact sensitivity are distinguished by polarized patterns of cytokine production: INF-γ producing (Tcl) effector CD8+ T cells and IL-4/11-10 producing (Th2) negative regulatory CD4+ T cells. J Exp Med 1996;183:1001–1012.PubMedCrossRefGoogle Scholar
  9. 9.
    Engeman TM, Gorbachev AV, Gladue RP, et al.: Inhibition of functional T cell priming and contact hypersensitivity responses by treatment with anti-secondary lymphoid chemokine antibody during hapten sensitization. J Immunol 2000;164:5207–5214.PubMedGoogle Scholar
  10. 10.
    Gunn MD, Kyuw S, Tam C, et al.: Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 1999;189: 451–460.PubMedCrossRefGoogle Scholar
  11. 11.
    Saeki H, Moore AM, Brown MJ, et al.: Secondary lymphoid-tissue chemokine (SLC) and CC chemokine receptor 7 (CCR7) participate in the emigration pathway of maturedendritic cells from the skin to regional lymphnodes. Immunol 1999;162:2472–2475.Google Scholar
  12. 12.
    Gocinski BL, Tigelaar RE: Roles of CD4+ and CD8+ T cells inmurine contact sensitivity revealed by in vivo monoclonal antibody depletion. J Immunol 1990;144: 4121–4128.PubMedGoogle Scholar
  13. 13.
    Bour H, Peyron E, Gaucherand, M, et al.: Major histocompatibility complex class I-restricted CD8+T cells and class II-restricted CD4+ T cells, respectively, mediate and regulate contact sensitivity to dintirofluorobenzene. Eur J Immunol 1995;25:3006–3010.PubMedCrossRefGoogle Scholar
  14. 14.
    O'Garra A: Cytoines induce the development of functionally beterogeneous T helper cell subsets. Cell 1998;8:275–283.Google Scholar
  15. 15.
    Chan S, Perussia B, Gupta J, et al. Induction of interferon-γ-production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med 1991; 173:869–879.PubMedCrossRefGoogle Scholar
  16. 16.
    Hsieh CS, Macatonia S, Tripp C, et al.: Development of Th1 CD4+ T cells through IL-12 producted by Listeria-induced macrophages. Science 1993;260:547–549.PubMedCrossRefGoogle Scholar
  17. 17.
    Manetti R, Parronchi P, Guidizi MG, et al.: Natural killer cell stimulatory factor [interleukin 12 (IL-12)] induces T helper type I (Th1)-specific immune responses and inhibits the development of IL-4-producing cells. J Exp Med 1993;177:1199.PubMedCrossRefGoogle Scholar
  18. 18.
    Dilulio NA, Xu H, Fairchild RL: IL-12, diverts development of CD4+ T cells from regulatory Th2 to effector Th1 cells in contact hypersensitivity. Eur J Immunol 1995;26:2006–2612.Google Scholar
  19. 19.
    Muller G, Saloga J, Germann T, et al.: IL-12 as mediator and adjuvant for the induction of contact sensitivity in vivo. J. Immunol 1995;155:4661–4668PubMedGoogle Scholar
  20. 20.
    Riemann H, Schwarz A, Grabbe S, et al.: Neutralization of IL-12 in vivo prevents induction, of contact hypersensitivity and induces hapten-specific tolerance. J Immunol 1996;156:1799–1803.PubMedGoogle Scholar
  21. 21.
    Xu H, Banerjee A, Dilulio NA, et al.: Development of effector CD8+ T cells in contact hypersensitivity occurs independently of CD4+ T cells. J Immunol 1997;158: 4721–4728.PubMedGoogle Scholar
  22. 22.
    Sher A, Coffman RL: Regulation of immunity to parasites by T cells and T cell-derived cytokines. Annu Rev Immunol 1992; 10:385–409.PubMedCrossRefGoogle Scholar
  23. 23.
    Trinchieri G: Cytokines acting on orsecreted by macrophages during intracellulaar infection (IL-10, IL-12, IFN-γ). Curr Opin Immunol 1997;9:17–23.PubMedCrossRefGoogle Scholar
  24. 24.
    Ferguson TA, Dube P, Griffith TS: Regulation of contact hypersensitivity by interleukin 10. J Exp Med 1994;179:1597–1604.PubMedCrossRefGoogle Scholar
  25. 25.
    Groux H, O'Garra A, Bigler M, et al.: A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–742.PubMedCrossRefGoogle Scholar
  26. 26.
    Kitani A, Chua K, Nakamura K, et al.: Activated self-MHC-reactive T cells have the cytokine phenotype of Th3/T regulatory cell 1 T cells. J Immunol 2000;165:691–702.PubMedGoogle Scholar
  27. 27.
    Powrie F, Carlino J, Leach MW, et al.: A critical role for transforming growth factor-β but not interleukin 4 in the suppression of T helpertype 1-mediated colitis by CD45RBkw CD4+ T cells. J Exp Med 1996; 183:2669–2674.PubMedCrossRefGoogle Scholar
  28. 28.
    Bennett SRM, Carbone FR, Karamalis F, et al.: Help for cytotoxic-T-cell responses: is mediated by CD40 signalling. Nature 1998; 393:478–480.PubMedCrossRefGoogle Scholar
  29. 29.
    Ridge JP, DiRosa F, Matzinger P: Aconditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killercell. Nature 1998;393:474–478.PubMedCrossRefGoogle Scholar
  30. 30.
    Schoenberger SP, Toes REM, van der Voort EIH, et al.: T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions. Nature 1998;393:480–483.PubMedCrossRefGoogle Scholar
  31. 31.
    Gorbachev AV, Heeger PS, Fairchild RL: CD4+ and CD8+ T cell priming for contact hypersensitivity occurs indeperndently of CD40-CD154 interactions. J Immunol 2001;166:2323–2332.PubMedGoogle Scholar
  32. 32.
    Ashany D, Savir A, Bhardwaj N, et al.: Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway. J Immunol 1999;163:5303–5311.PubMedGoogle Scholar
  33. 33.
    Koppi TA, Tough-Bement T, Lewinsohn DM, et al.: CD40 ligand inhibits Fas/CD95-mediated apoptosis of human blood-derived dendritic cells. Eur J Immunol 1997;27:3161–3165.PubMedCrossRefGoogle Scholar
  34. 34.
    Kawamura T, Azuma M, Kayagaki N, et al.: Fas/Fas ligand-mediated elimination of antigen-bearing Langerhans cells in draining lymph nodes. Br J Dermatol 1999;141: 201–205.PubMedCrossRefGoogle Scholar
  35. 35.
    Traidl C, Sebastiani S, Albanesi C, et al.: Disparate cytotoxic activity of nickel-specific CD8+ and CD4+ T cell subsets against keratinocytes. J Immunol 2000;165:3058–3064.PubMedGoogle Scholar
  36. 36.
    Cohen PL, Eisenberg RA: Lpr and gld: Single gene models of systemic autoimmununity and lymphoproliferative disease. Annu Rev Immunol 1991;9:243–269.PubMedCrossRefGoogle Scholar
  37. 37.
    Krammer PH: CD95's deadly mission in the immune system. Nature 2000;407:789–795.PubMedCrossRefGoogle Scholar
  38. 38.
    Van der Bruggen P, Travesari C, Chomez P, et al.: A gene encoding an antigen recognized by cytolytic T lymphocytes on human melanoma. Sciece 1991;254: 1643–1646.CrossRefGoogle Scholar
  39. 39.
    Goulmy E, Gratama JW, Blokland E, et al.: A minor transplantation antigen detected by MHC restricted cytotoxic T lymphocytes during graft versus host disease. Nature 1983;302: 159–162.PubMedCrossRefGoogle Scholar
  40. 40.
    Sprent J, Schaefer M, Gao E-K, et al.: Role of T cell subsets in lethal graft-versus-host disease (GVHD) directed to class I versus class II H-2 differences. J Exp Med 1988; 167:556–569.PubMedCrossRefGoogle Scholar
  41. 41.
    Gottlieb SL, Gilleaudeau P, Johnson R, et al.: Response of psoriasis to a lymphocte selective toxin (DAB 389 IL-2) suggests a primary immune, but not keratiinocyte, pathogenic basis. Nature Med 1995;1:442–447.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2001

Authors and Affiliations

  • Anton V. Gorbachev
    • 1
  • Robert L. Fairchild
    • 1
  1. 1.Department of Immunology, Lerner Research InstituteThe Cleveland Clinic FoundationCleveland

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