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J Clin Invest. 1996 August 1; 98(3): 715–722.
PMCID: PMC507481

IL-12 in conjunction with dendritic cells enhances antiviral CD8+ CTL responses in vitro.

Abstract

CD8+ cytolytic T lymphocytes (CTLs) are important mediators for resistance to infections and malignant diseases. IL-12 enhances proliferative and cytolytic responses by killer cells, but its function in the generation of human antiviral CD8+ T cell responses has not been defined. We therefore evaluated the role of IL-12 in the generation of CTLs to influenza-infected dendritic cells. IL-12 was not detectable in supernatants of infected-dendritic cells, or during CTL generation. Furthermore, anti-IL-12 antibody did not block CTL generation. However, exogenous IL-12 (30-300 pg/ml) enhanced CD8+ T cell proliferative and cytolytic responses. The effect was greatest in individuals with weak reactivity to influenza virus or at antigen-presenting cell (APC):T cell ratios of 1:100 or less. IL-12 augmented interferon-gamma production during CTL generation. The CTL enhancing effects of the cytokine, however, could not be blocked by neutralizing anti-interferon-gamma antibody. Together with IL-12, antigen-pulsed dendritic cells may be a useful approach for boosting CTL responses against infectious agents and malignancies.

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Selected References

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  • Trinchieri G. Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol. 1995;13:251–276. [PubMed]
  • 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]
  • Scharton TM, Scott P. Natural killer cells are a source of interferon gamma that drives differentiation of CD4+ T cell subsets and induces early resistance to Leishmania major in mice. J Exp Med. 1993 Aug 1;178(2):567–577. [PMC free article] [PubMed]
  • Chehimi J, Valiante NM, D'Andrea A, Rengaraju M, Rosado Z, Kobayashi M, Perussia B, Wolf SF, Starr SE, Trinchieri G. Enhancing effect of natural killer cell stimulatory factor (NKSF/interleukin-12) on cell-mediated cytotoxicity against tumor-derived and virus-infected cells. Eur J Immunol. 1993 Aug;23(8):1826–1830. [PubMed]
  • Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospísil M, Young HA, Wolf SF, Young D, Clark SC, Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991 Apr 1;173(4):869–879. [PMC free article] [PubMed]
  • Kobayashi M, Fitz L, Ryan M, Hewick RM, Clark SC, Chan S, Loudon R, Sherman F, Perussia B, Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. [PMC free article] [PubMed]
  • Gately MK, Desai BB, Wolitzky AG, Quinn PM, Dwyer CM, Podlaski FJ, Familletti PC, Sinigaglia F, Chizonnite R, Gubler U, et al. Regulation of human lymphocyte proliferation by a heterodimeric cytokine, IL-12 (cytotoxic lymphocyte maturation factor). J Immunol. 1991 Aug 1;147(3):874–882. [PubMed]
  • Seder RA, Paul WE. Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu Rev Immunol. 1994;12:635–673. [PubMed]
  • Gately MK, Wolitzky AG, Quinn PM, Chizzonite R. Regulation of human cytolytic lymphocyte responses by interleukin-12. Cell Immunol. 1992 Aug;143(1):127–142. [PubMed]
  • Chouaib S, Chehimi J, Bani L, Genetet N, Tursz T, Gay F, Trinchieri G, Mami-Chouaib F. Interleukin 12 induces the differentiation of major histocompatibility complex class I-primed cytotoxic T-lymphocyte precursors into allospecific cytotoxic effectors. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12659–12663. [PubMed]
  • Bloom ET, Horvath JA. Cellular and molecular mechanisms of the IL-12-induced increase in allospecific murine cytolytic T cell activity. Implications for the age-related decline in CTL. J Immunol. 1994 May 1;152(9):4242–4254. [PubMed]
  • Mehrotra PT, Wu D, Crim JA, Mostowski HS, Siegel JP. Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes. J Immunol. 1993 Sep 1;151(5):2444–2452. [PubMed]
  • Bhardwaj N, Bender A, Gonzalez N, Bui LK, Garrett MC, Steinman RM. 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. [PMC free article] [PubMed]
  • Bender A, Bui LK, Feldman MA, Larsson M, Bhardwaj N. Inactivated influenza virus, when presented on dendritic cells, elicits human CD8+ cytolytic T cell responses. J Exp Med. 1995 Dec 1;182(6):1663–1671. [PMC free article] [PubMed]
  • Macatonia SE, Hosken NA, Litton M, Vieira P, Hsieh CS, Culpepper JA, Wysocka M, Trinchieri G, Murphy KM, O'Garra A. Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. J Immunol. 1995 May 15;154(10):5071–5079. [PubMed]
  • Kang K, Kubin M, Cooper KD, Lessin SR, Trinchieri G, Rook AH. IL-12 synthesis by human Langerhans cells. J Immunol. 1996 Feb 15;156(4):1402–1407. [PubMed]
  • Kanangat S, Nair S, Babu JS, Rouse BT. Expression of cytokine mRNA in murine splenic dendritic cells and better induction of T cell-derived cytokines by dendritic cells than by macrophages during in vitro costimulation assay using specific antigens. J Leukoc Biol. 1995 Feb;57(2):310–316. [PubMed]
  • Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R, Anderson D, Eisenmann J, Grabstein K, Caligiuri MA. Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med. 1994 Oct 1;180(4):1395–1403. [PMC free article] [PubMed]
  • Seder RA, Grabstein KH, Berzofsky JA, McDyer JF. Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15. J Exp Med. 1995 Oct 1;182(4):1067–1077. [PMC free article] [PubMed]
  • Fesq H, Bacher M, Nain M, Gemsa D. Programmed cell death (apoptosis) in human monocytes infected by influenza A virus. Immunobiology. 1994 Feb;190(1-2):175–182. [PubMed]
  • Celis E, Tsai V, Crimi C, DeMars R, Wentworth PA, Chesnut RW, Grey HM, Sette A, Serra HM. Induction of anti-tumor cytotoxic T lymphocytes in normal humans using primary cultures and synthetic peptide epitopes. Proc Natl Acad Sci U S A. 1994 Mar 15;91(6):2105–2109. [PubMed]
  • Steinman RM. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. [PubMed]
  • Shu U, Kiniwa M, Wu CY, Maliszewski C, Vezzio N, Hakimi J, Gately M, Delespesse G. Activated T cells induce interleukin-12 production by monocytes via CD40-CD40 ligand interaction. Eur J Immunol. 1995 Apr;25(4):1125–1128. [PubMed]
  • Stuber E, Strober W, Neurath M. Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion. J Exp Med. 1996 Feb 1;183(2):693–698. [PMC free article] [PubMed]
  • Young JW, Steinman RM. Dendritic cells stimulate primary human cytolytic lymphocyte responses in the absence of CD4+ helper T cells. J Exp Med. 1990 Apr 1;171(4):1315–1332. [PMC free article] [PubMed]
  • Clerici M, Lucey DR, Berzofsky JA, Pinto LA, Wynn TA, Blatt SP, Dolan MJ, Hendrix CW, Wolf SF, Shearer GM. Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro. Science. 1993 Dec 10;262(5140):1721–1724. [PubMed]
  • Robertson MJ, Soiffer RJ, Wolf SF, Manley TJ, Donahue C, Young D, Herrmann SH, Ritz J. Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differentially regulated by NKSF. J Exp Med. 1992 Mar 1;175(3):779–788. [PMC free article] [PubMed]
  • Orange JS, Biron CA. An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol. 1996 Feb 1;156(3):1138–1142. [PubMed]
  • Müller U, Steinhoff U, Reis LF, Hemmi S, Pavlovic J, Zinkernagel RM, Aguet M. Functional role of type I and type II interferons in antiviral defense. Science. 1994 Jun 24;264(5167):1918–1921. [PubMed]
  • Guidotti LG, Ishikawa T, Hobbs MV, Matzke B, Schreiber R, Chisari FV. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 1996 Jan;4(1):25–36. [PubMed]
  • Horohov DW, Crim JA, Smith PL, Siegel JP. IL-4 (B cell-stimulatory factor 1) regulates multiple aspects of influenza virus-specific cell-mediated immunity. J Immunol. 1988 Dec 15;141(12):4217–4223. [PubMed]
  • D'Andrea A, Ma X, Aste-Amezaga M, Paganin C, Trinchieri G. Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production. J Exp Med. 1995 Feb 1;181(2):537–546. [PMC free article] [PubMed]
  • Coutelier JP, Van Broeck J, Wolf SF. Interleukin-12 gene expression after viral infection in the mouse. J Virol. 1995 Mar;69(3):1955–1958. [PMC free article] [PubMed]
  • Orange JS, Wolf SF, Biron CA. Effects of IL-12 on the response and susceptibility to experimental viral infections. J Immunol. 1994 Feb 1;152(3):1253–1264. [PubMed]
  • Chehimi J, Starr SE, Frank I, D'Andrea A, Ma X, MacGregor RR, Sennelier J, Trinchieri G. Impaired interleukin 12 production in human immunodeficiency virus-infected patients. J Exp Med. 1994 Apr 1;179(4):1361–1366. [PMC free article] [PubMed]
  • Yamada YK, Meager A, Yamada A, Ennis FA. Human interferon alpha and gamma production by lymphocytes during the generation of influenza virus-specific cytotoxic T lymphocytes. J Gen Virol. 1986 Nov;67(Pt 11):2325–2334. [PubMed]
  • McMichael A. Cytotoxic T lymphocytes specific for influenza virus. Curr Top Microbiol Immunol. 1994;189:75–91. [PubMed]
  • Paglia P, Chiodoni C, Rodolfo M, Colombo MP. Murine dendritic cells loaded in vitro with soluble protein prime cytotoxic T lymphocytes against tumor antigen in vivo. J Exp Med. 1996 Jan 1;183(1):317–322. [PMC free article] [PubMed]
  • Mayordomo JI, Zorina T, Storkus WJ, Zitvogel L, Celluzzi C, Falo LD, Melief CJ, Ildstad ST, Kast WM, Deleo AB, et al. Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity. Nat Med. 1995 Dec;1(12):1297–1302. [PubMed]
  • Celluzzi CM, Mayordomo JI, Storkus WJ, Lotze MT, Falo LD., Jr Peptide-pulsed dendritic cells induce antigen-specific CTL-mediated protective tumor immunity. J Exp Med. 1996 Jan 1;183(1):283–287. [PMC free article] [PubMed]
  • Orange JS, Salazar-Mather TP, Opal SM, Spencer RL, Miller AH, McEwen BS, Biron CA. Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids. J Exp Med. 1995 Mar 1;181(3):901–914. [PMC free article] [PubMed]

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