Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Mar 15;97(6):1550–1555. doi: 10.1172/JCI118578

Modulation of T cell responses to recall antigens presented by Langerhans cells in HIV-discordant identical twins by anti-interleukin (IL)-10 antibodies and IL-12.

A Blauvelt 1, C Chougnet 1, G M Shearer 1, S I Katz 1
PMCID: PMC507216  PMID: 8617889

Abstract

Decreased antigen (Ag)-specific T cell (TC) proliferation and IL-2 production are detected in all stages of HIV disease. To determine whether dendritic cell dysfunction and/or abnormal cytokine production contribute to HIV-induced immune dysregulation, we studies TC responses to recall Ags (influenza virus and tetanus toxoid) presented by Langerhans cells (LC) in six pairs of HIV-discordant identical twins, and the modulation of these responses by anti-IL-10 (alphaIL-10) mAbs and IL-12. LC from HIV+ twins induced IL-2 comparable to normal LC in cultures containing TC from uninfected twins. In contrast, IL-2 production was markedly decreased in cultures containing TC from HIV+ twins. IL-12 enhanced Ag-specific IL-2 production by TC from two patients with CD4+ counts > 600. In contrast, alphaIL-10 mAbs enhanced IL-2 production in influenza virus-stimulated cultures containing TC from two patients with CD4+ counts < 20. Thus, these findings suggest that immunologic dysfunction of dendritic cells does not contribute to impaired secondary immune responses in HIV+ individuals. Although few patients were studied, partial immune reconstitution in vitro, as demonstrated here, may help to predict those individuals who might benefit from cytokines or antibodies against cytokines as immunotherapy for HIV disease.

Full Text

The Full Text of this article is available as a PDF (189.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Akridge R. E., Oyafuso L. K., Reed S. G. IL-10 is induced during HIV-1 infection and is capable of decreasing viral replication in human macrophages. J Immunol. 1994 Dec 15;153(12):5782–5789. [PubMed] [Google Scholar]
  2. Barcellini W., Rizzardi G. P., Velati C., Borghi M. O., Fain C., Lazzarin A., Meroni P. L. In vitro production of type 1 and type 2 cytokines by peripheral blood mononuclear cells from high-risk HIV-negative intravenous drug users. AIDS. 1995 Jul;9(7):691–694. doi: 10.1097/00002030-199507000-00004. [DOI] [PubMed] [Google Scholar]
  3. Beissert S., Hosoi J., Grabbe S., Asahina A., Granstein R. D. IL-10 inhibits tumor antigen presentation by epidermal antigen-presenting cells. J Immunol. 1995 Feb 1;154(3):1280–1286. [PubMed] [Google Scholar]
  4. Berger R., Gartner S., Rappersberger K., Foster C. A., Wolff K., Stingl G. Isolation of human immunodeficiency virus type 1 from human epidermis: virus replication and transmission studies. J Invest Dermatol. 1992 Sep;99(3):271–277. doi: 10.1111/1523-1747.ep12616619. [DOI] [PubMed] [Google Scholar]
  5. Bhardwaj N., Bender A., Gonzalez N., Bui L. K., Garrett M. C., Steinman R. M. Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells. J Clin Invest. 1994 Aug;94(2):797–807. doi: 10.1172/JCI117399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blauvelt A., Clerici M., Lucey D. R., Steinberg S. M., Yarchoan R., Walker R., Shearer G. M., Katz S. I. Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons. J Immunol. 1995 Apr 1;154(7):3506–3515. [PubMed] [Google Scholar]
  7. Borghi P., Fantuzzi L., Varano B., Gessani S., Puddu P., Conti L., Capobianchi M. R., Ameglio F., Belardelli F. Induction of interleukin-10 by human immunodeficiency virus type 1 and its gp120 protein in human monocytes/macrophages. J Virol. 1995 Feb;69(2):1284–1287. doi: 10.1128/jvi.69.2.1284-1287.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cameron P. U., Forsum U., Teppler H., Granelli-Piperno A., Steinman R. M. During HIV-1 infection most blood dendritic cells are not productively infected and can induce allogeneic CD4+ T cells clonal expansion. Clin Exp Immunol. 1992 May;88(2):226–236. doi: 10.1111/j.1365-2249.1992.tb03066.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cameron P. U., Freudenthal P. S., Barker J. M., Gezelter S., Inaba K., Steinman R. M. Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science. 1992 Jul 17;257(5068):383–387. doi: 10.1126/science.1352913. [DOI] [PubMed] [Google Scholar]
  10. Cameron P. U., Pope M., Gezelter S., Steinman R. M. Infection and apoptotic cell death of CD4+ T cells during an immune response to HIV-1-pulsed dendritic cells. AIDS Res Hum Retroviruses. 1994 Jan;10(1):61–71. doi: 10.1089/aid.1994.10.61. [DOI] [PubMed] [Google Scholar]
  11. Chehimi J., Prakash K., Shanmugam V., Collman R., Jackson S. J., Bandyopadhyay S., Starr S. E. CD4-independent infection of human peripheral blood dendritic cells with isolates of human immunodeficiency virus type 1. J Gen Virol. 1993 Jul;74(Pt 7):1277–1285. doi: 10.1099/0022-1317-74-7-1277. [DOI] [PubMed] [Google Scholar]
  12. Chehimi J., Starr S. E., Frank I., D'Andrea A., Ma X., MacGregor R. R., Sennelier J., Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. doi: 10.1084/jem.179.4.1361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Chehimi J., Starr S. E., Frank I., Rengaraju M., Jackson S. J., Llanes C., Kobayashi M., Perussia B., Young D., Nickbarg E. Natural killer (NK) cell stimulatory factor increases the cytotoxic activity of NK cells from both healthy donors and human immunodeficiency virus-infected patients. J Exp Med. 1992 Mar 1;175(3):789–796. doi: 10.1084/jem.175.3.789. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chehimi J., Trinchieri G. Interleukin-12: a bridge between innate resistance and adaptive immunity with a role in infection and acquired immunodeficiency. J Clin Immunol. 1994 May;14(3):149–161. doi: 10.1007/BF01533364. [DOI] [PubMed] [Google Scholar]
  15. Chernoff A. E., Granowitz E. V., Shapiro L., Vannier E., Lonnemann G., Angel J. B., Kennedy J. S., Rabson A. R., Wolff S. M., Dinarello C. A. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995 May 15;154(10):5492–5499. [PubMed] [Google Scholar]
  16. Cimarelli A., Zambruno G., Marconi A., Girolomoni G., Bertazzoni U., Giannetti A. Quantitation by competitive PCR of HIV-1 proviral DNA in epidermal Langerhans cells of HIV-infected patients. J Acquir Immune Defic Syndr. 1994 Mar;7(3):230–235. [PubMed] [Google Scholar]
  17. Clerici M., Hakim F. T., Venzon D. J., Blatt S., Hendrix C. W., Wynn T. A., Shearer G. M. Changes in interleukin-2 and interleukin-4 production in asymptomatic, human immunodeficiency virus-seropositive individuals. J Clin Invest. 1993 Mar;91(3):759–765. doi: 10.1172/JCI116294. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Clerici M., Lucey D. R., Berzofsky J. A., Pinto L. A., Wynn T. A., Blatt S. P., Dolan M. J., Hendrix C. W., Wolf S. F., Shearer G. M. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. doi: 10.1126/science.7903123. [DOI] [PubMed] [Google Scholar]
  19. Clerici M., Shearer G. M. A TH1-->TH2 switch is a critical step in the etiology of HIV infection. Immunol Today. 1993 Mar;14(3):107–111. doi: 10.1016/0167-5699(93)90208-3. [DOI] [PubMed] [Google Scholar]
  20. Clerici M., Shearer G. M. The Th1-Th2 hypothesis of HIV infection: new insights. Immunol Today. 1994 Dec;15(12):575–581. doi: 10.1016/0167-5699(94)90220-8. [DOI] [PubMed] [Google Scholar]
  21. Clerici M., Stocks N. I., Zajac R. A., Boswell R. N., Lucey D. R., Via C. S., Shearer G. M. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest. 1989 Dec;84(6):1892–1899. doi: 10.1172/JCI114376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Clerici M., Stocks N. I., Zajac R. A., Boswell R. N., Shearer G. M. Accessory cell function in asymptomatic human immunodeficiency virus-infected patients. Clin Immunol Immunopathol. 1990 Feb;54(2):168–173. doi: 10.1016/0090-1229(90)90078-5. [DOI] [PubMed] [Google Scholar]
  23. Clerici M., Wynn T. A., Berzofsky J. A., Blatt S. P., Hendrix C. W., Sher A., Coffman R. L., Shearer G. M. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. J Clin Invest. 1994 Feb;93(2):768–775. doi: 10.1172/JCI117031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Cooper K. D., Neises G. R., Katz S. I. Antigen-presenting OKM5+ melanophages appear in human epidermis after ultraviolet radiation. J Invest Dermatol. 1986 Apr;86(4):363–370. doi: 10.1111/1523-1747.ep12285600. [DOI] [PubMed] [Google Scholar]
  25. Ding L., Linsley P. S., Huang L. Y., Germain R. N., Shevach E. M. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol. 1993 Aug 1;151(3):1224–1234. [PubMed] [Google Scholar]
  26. Eales L. J., Farrant J., Helbert M., Pinching A. J. Peripheral blood dendritic cells in persons with AIDS and AIDS related complex: loss of high intensity class II antigen expression and function. Clin Exp Immunol. 1988 Mar;71(3):423–427. [PMC free article] [PubMed] [Google Scholar]
  27. Enk A. H., Angeloni V. L., Udey M. C., Katz S. I. Inhibition of Langerhans cell antigen-presenting function by IL-10. A role for IL-10 in induction of tolerance. J Immunol. 1993 Sep 1;151(5):2390–2398. [PubMed] [Google Scholar]
  28. Erard F., Dunbar P. R., Le Gros G. The IL4- induced switch of CD8+ T cells to a TH2 phenotype and its possible relationship to the onset of AIDS. Res Immunol. 1994 Oct-Dec;145(8-9):643–646. doi: 10.1016/s0923-2494(05)80047-1. [DOI] [PubMed] [Google Scholar]
  29. Fauci A. S. AIDS: immunopathogenic mechanisms and research strategies. Clin Res. 1987 Oct;35(6):503–510. [PubMed] [Google Scholar]
  30. Ferbas J. J., Toso J. F., Logar A. J., Navratil J. S., Rinaldo C. R., Jr CD4+ blood dendritic cells are potent producers of IFN-alpha in response to in vitro HIV-1 infection. J Immunol. 1994 May 1;152(9):4649–4662. [PubMed] [Google Scholar]
  31. Germann T., Gately M. K., Schoenhaut D. S., Lohoff M., Mattner F., Fischer S., Jin S. C., Schmitt E., Rüde E. Interleukin-12/T cell stimulating factor, a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells. Eur J Immunol. 1993 Aug;23(8):1762–1770. doi: 10.1002/eji.1830230805. [DOI] [PubMed] [Google Scholar]
  32. Giannetti A., Zambruno G., Cimarelli A., Marconi A., Negroni M., Girolomoni G., Bertazzoni U. Direct detection of HIV-1 RNA in epidermal Langerhans cells of HIV-infected patients. J Acquir Immune Defic Syndr. 1993 Apr;6(4):329–333. [PubMed] [Google Scholar]
  33. Graziosi C., Pantaleo G., Gantt K. R., Fortin J. P., Demarest J. F., Cohen O. J., Sékaly R. P., Fauci A. S. Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994 Jul 8;265(5169):248–252. doi: 10.1126/science.8023143. [DOI] [PubMed] [Google Scholar]
  34. Helbert M. R., L'age-Stehr J., Mitchison N. A. Antigen presentation, loss of immunological memory and AIDS. Immunol Today. 1993 Jul;14(7):340–344. doi: 10.1016/0167-5699(93)90232-A. [DOI] [PubMed] [Google Scholar]
  35. Henry M., Uthman A., Ballaun C., Stingl G., Tschachler E. Epidermal langerhans cells of AIDS patients express HIV-1 regulatory and structural genes. J Invest Dermatol. 1994 Oct;103(4):593–596. doi: 10.1111/1523-1747.ep12396918. [DOI] [PubMed] [Google Scholar]
  36. Hofmann B., Odum N., Jakobsen B. K., Platz P., Ryder L. P., Nielsen J. O., Gerstoft J., Svejgaard A. Immunological studies in the acquired immunodeficiency syndrome. II. Active suppression or intrinsic defect--investigated by mixing AIDS cells with HLA-DR identical normal cells. Scand J Immunol. 1986 Jun;23(6):669–678. doi: 10.1111/j.1365-3083.1986.tb02003.x. [DOI] [PubMed] [Google Scholar]
  37. Knight S. C., Macatonia S. E., Patterson S. HIV I infection of dendritic cells. Int Rev Immunol. 1990;6(2-3):163–175. doi: 10.3109/08830189009056627. [DOI] [PubMed] [Google Scholar]
  38. Kootstra N. A., van 't Wout A., Huisman H. G., Miedema F., Schuitemaker H. Interference of interleukin-10 with human immunodeficiency virus type 1 replication in primary monocyte-derived macrophages. J Virol. 1994 Nov;68(11):6967–6975. doi: 10.1128/jvi.68.11.6967-6975.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Langhoff E., Terwilliger E. F., Bos H. J., Kalland K. H., Poznansky M. C., Bacon O. M., Haseltine W. A. Replication of human immunodeficiency virus type 1 in primary dendritic cell cultures. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):7998–8002. doi: 10.1073/pnas.88.18.7998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Macatonia S. E., Gompels M., Pinching A. J., Patterson S., Knight S. C. Antigen-presentation by macrophages but not by dendritic cells in human immunodeficiency virus (HIV) infection. Immunology. 1992 Apr;75(4):576–581. [PMC free article] [PubMed] [Google Scholar]
  41. Macatonia S. E., Lau R., Patterson S., Pinching A. J., Knight S. C. Dendritic cell infection, depletion and dysfunction in HIV-infected individuals. Immunology. 1990 Sep;71(1):38–45. [PMC free article] [PubMed] [Google Scholar]
  42. Macatonia S. E., Patterson S., Knight S. C. Suppression of immune responses by dendritic cells infected with HIV. Immunology. 1989 Jul;67(3):285–289. [PMC free article] [PubMed] [Google Scholar]
  43. Masood R., Lunardi-Iskandar Y., Moudgil T., Zhang Y., Law R. E., Huang C. L., Puri R. K., Levine A. M., Gill P. S. IL-10 inhibits HIV-1 replication and is induced by tat. Biochem Biophys Res Commun. 1994 Jul 15;202(1):374–383. doi: 10.1006/bbrc.1994.1938. [DOI] [PubMed] [Google Scholar]
  44. Matsuda M., Salazar F., Petersson M., Masucci G., Hansson J., Pisa P., Zhang Q. J., Masucci M. G., Kiessling R. Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med. 1994 Dec 1;180(6):2371–2376. doi: 10.1084/jem.180.6.2371. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Meyaard L., Otto S. A., Keet I. P., van Lier R. A., Miedema F. Changes in cytokine secretion patterns of CD4+ T-cell clones in human immunodeficiency virus infection. Blood. 1994 Dec 15;84(12):4262–4268. [PubMed] [Google Scholar]
  46. Meyaard L., Schuitemaker H., Miedema F. T-cell dysfunction in HIV infection: anergy due to defective antigen-presenting cell function? Immunol Today. 1993 Apr;14(4):161–164. doi: 10.1016/0167-5699(93)90279-T. [DOI] [PubMed] [Google Scholar]
  47. Mitra R. S., Judge T. A., Nestle F. O., Turka L. A., Nickoloff B. J. Psoriatic skin-derived dendritic cell function is inhibited by exogenous IL-10. Differential modulation of B7-1 (CD80) and B7-2 (CD86) expression. J Immunol. 1995 Mar 15;154(6):2668–2677. [PubMed] [Google Scholar]
  48. Montaner L. J., Griffin P., Gordon S. Interleukin-10 inhibits initial reverse transcription of human immunodeficiency virus type 1 and mediates a virostatic latent state in primary blood-derived human macrophages in vitro. J Gen Virol. 1994 Dec;75(Pt 12):3393–3400. doi: 10.1099/0022-1317-75-12-3393. [DOI] [PubMed] [Google Scholar]
  49. Paganelli R., Scala E., Ansotegui I. J., Ausiello C. M., Halapi E., Fanales-Belasio E., D'Offizi G., Mezzaroma I., Pandolfi F., Fiorilli M. CD8+ T lymphocytes provide helper activity for IgE synthesis in human immunodeficiency virus-infected patients with hyper-IgE. J Exp Med. 1995 Jan 1;181(1):423–428. doi: 10.1084/jem.181.1.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Pinchuk L. M., Polacino P. S., Agy M. B., Klaus S. J., Clark E. A. The role of CD40 and CD80 accessory cell molecules in dendritic cell-dependent HIV-1 infection. Immunity. 1994 Jul;1(4):317–325. doi: 10.1016/1074-7613(94)90083-3. [DOI] [PubMed] [Google Scholar]
  51. Pope M., Betjes M. G., Romani N., Hirmand H., Cameron P. U., Hoffman L., Gezelter S., Schuler G., Steinman R. M. Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell. 1994 Aug 12;78(3):389–398. doi: 10.1016/0092-8674(94)90418-9. [DOI] [PubMed] [Google Scholar]
  52. Rich E. A., Toossi Z., Fujiwara H., Hanigosky R., Lederman M. M., Ellner J. J. Defective accessory function of monocytes in human immunodeficiency virus-related disease syndromes. J Lab Clin Med. 1988 Aug;112(2):174–181. [PubMed] [Google Scholar]
  53. Saville M. W., Taga K., Foli A., Broder S., Tosato G., Yarchoan R. Interleukin-10 suppresses human immunodeficiency virus-1 replication in vitro in cells of the monocyte/macrophage lineage. Blood. 1994 Jun 15;83(12):3591–3599. [PubMed] [Google Scholar]
  54. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  55. Stingl G., Rappersberger K., Tschachler E., Gartner S., Groh V., Mann D. L., Wolff K., Popovic M. Langerhans cells in HIV-1 infection. J Am Acad Dermatol. 1990 Jun;22(6 Pt 2):1210–1217. doi: 10.1016/0190-9622(90)70165-e. [DOI] [PubMed] [Google Scholar]
  56. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 1994 Dec 15;84(12):4008–4027. [PubMed] [Google Scholar]
  57. Tschachler E., Groh V., Popovic M., Mann D. L., Konrad K., Safai B., Eron L., diMarzo Veronese F., Wolff K., Stingl G. Epidermal Langerhans cells--a target for HTLV-III/LAV infection. J Invest Dermatol. 1987 Feb;88(2):233–237. doi: 10.1111/1523-1747.ep12525402. [DOI] [PubMed] [Google Scholar]
  58. Weissman D., Li Y., Ananworanich J., Zhou L. J., Adelsberger J., Tedder T. F., Baseler M., Fauci A. S. Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):826–830. doi: 10.1073/pnas.92.3.826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Weissman D., Poli G., Fauci A. S. Interleukin 10 blocks HIV replication in macrophages by inhibiting the autocrine loop of tumor necrosis factor alpha and interleukin 6 induction of virus. AIDS Res Hum Retroviruses. 1994 Oct;10(10):1199–1206. doi: 10.1089/aid.1994.10.1199. [DOI] [PubMed] [Google Scholar]
  60. Zhang M., Gong J., Iyer D. V., Jones B. E., Modlin R. L., Barnes P. F. T cell cytokine responses in persons with tuberculosis and human immunodeficiency virus infection. J Clin Invest. 1994 Dec;94(6):2435–2442. doi: 10.1172/JCI117611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. de Waal Malefyt R., Haanen J., Spits H., Roncarolo M. G., te Velde A., Figdor C., Johnson K., Kastelein R., Yssel H., de Vries J. E. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med. 1991 Oct 1;174(4):915–924. doi: 10.1084/jem.174.4.915. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES