Search tips
Search criteria 


Logo of iaiPermissionsJournals.ASM.orgJournalIAI ArticleJournal InfoAuthorsReviewers
Infect Immun. 1996 May; 64(5): 1595–1599.
PMCID: PMC173967

gamma Interferon gene expression and release in human lymphocytes directly activated by Cryptococcus neoformans and Candida albicans.


Previous studies in our laboratory and others have demonstrated that T and/or NK cells can directly bind to and inhibit the growth of the medically important fungal pathogens Cryptococcus neoformans and Candida albicans by apparently non-major histocompatibility complex-restricted mechanisms. Here, we examined whether this direct interaction between lymphocytes and fungi also results in cytokine gene expression and release. Nonadherent lymphocytes (NAL), isolated from human peripheral blood mononuclear cells by depletion of cells adherent to plastic and nylon wool, released gamma interferon (IFN-gamma), but not interleukin-4 (IL-4) and IL-10, following stimulation with C. neoformans yeast cells and C. albicans yeast cells, hyphae, and supernatants. The fungal stimuli also induced IFN-gamma mRNA, with peak gene expression seen at or after 18 h. IFN-gamma release was still seen even when either NK cells or T lymphocytes were depleted by negative selection, suggesting that both cell types can be stimulated by fungi to produce IFN-gamma. Release of IFN-gamma from fungus-stimulated NAL occurred in the absence of an intact complement system and was not especially enhanced by culture with IL-2 or IL-12. These data expand the mechanisms by which the direct interaction of NAL with fungal targets can lead to immune activation. Moreover, to our knowledge, this is the first demonstration of direct stimulation of T-cell cytokine release by microbial pathogens.

Full Text

The Full Text of this article is available as a PDF (320K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Arancia G, Molinari A, Crateri P, Stringaro A, Ramoni C, Dupuis ML, Gomez MJ, Torosantucci A, Cassone A. Noninhibitory binding of human interleukin-2-activated natural killer cells to the germ tube forms of Candida albicans. Infect Immun. 1995 Jan;63(1):280–288. [PMC free article] [PubMed]
  • Ausiello CM, Urbani F, Gessani S, Spagnoli GC, Gomez MJ, Cassone A. Cytokine gene expression in human peripheral blood mononuclear cells stimulated by mannoprotein constituents from Candida albicans. Infect Immun. 1993 Oct;61(10):4105–4111. [PMC free article] [PubMed]
  • Beno DW, Mathews HL. Growth inhibition of Candida albicans by interleukin-2-induced lymph node cells. Cell Immunol. 1990 Jun;128(1):89–100. [PubMed]
  • Beno DW, Mathews HL. Growth inhibition of Candida albicans by interleukin-2-activated splenocytes. Infect Immun. 1992 Mar;60(3):853–863. [PMC free article] [PubMed]
  • Beno DW, Stöver AG, Mathews HL. Growth inhibition of Candida albicans hyphae by CD8+ lymphocytes. J Immunol. 1995 May 15;154(10):5273–5281. [PubMed]
  • Blanchard DK, Michelini-Norris MB, Djeu JY. Production of granulocyte-macrophage colony-stimulating factor by large granular lymphocytes stimulated with Candida albicans: role in activation of human neutrophil function. Blood. 1991 May 15;77(10):2259–2265. [PubMed]
  • Chong AS, Boussy IA, Graf LH, Scuderi P. Stimulation of IFN-gamma, TNF-alpha, and TNF-beta secretion in IL-2-activated T cells: costimulatory roles for LFA-1, LFA-2, CD44, and CD45 molecules. Cell Immunol. 1992 Oct 1;144(1):69–79. [PubMed]
  • Chong AS, Staren ED, Scuderi P. Monoclonal antibodies anti-CD3, anti-TCR alpha beta and anti-CD2 act synergistically with tumor cells to stimulate lymphokine-activated killer cells and tumor-infiltrating lymphocytes to secrete interferon gamma. Cancer Immunol Immunother. 1992;35(5):335–341. [PubMed]
  • Diamond RD, Lyman CA, Wysong DR. Disparate effects of interferon-gamma and tumor necrosis factor-alpha on early neutrophil respiratory burst and fungicidal responses to Candida albicans hyphae in vitro. J Clin Invest. 1991 Feb;87(2):711–720. [PMC free article] [PubMed]
  • Djeu JY, Blanchard DK. Regulation of human polymorphonuclear neutrophil (PMN) activity against Candida albicans by large granular lymphocytes via release of a PMN-activating factor. J Immunol. 1987 Oct 15;139(8):2761–2767. [PubMed]
  • Djeu JY, Blanchard DK, Richards AL, Friedman H. Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes. J Immunol. 1988 Dec 1;141(11):4047–4052. [PubMed]
  • Flesch IE, Schwamberger G, Kaufmann SH. Fungicidal activity of IFN-gamma-activated macrophages. Extracellular killing of Cryptococcus neoformans. J Immunol. 1989 May 1;142(9):3219–3224. [PubMed]
  • Hardy KJ, Manger B, Newton M, Stobo JD. Molecular events involved in regulating human interferon-gamma gene expression during T cell activation. J Immunol. 1987 Apr 1;138(7):2353–2358. [PubMed]
  • Hardy KJ, Peterlin BM, Atchison RE, Stobo JD. Regulation of expression of the human interferon gamma gene. Proc Natl Acad Sci U S A. 1985 Dec;82(23):8173–8177. [PubMed]
  • Harrison TS, Kornfeld H, Levitz SM. The effect of infection with human immunodeficiency virus on the anticryptococcal activity of lymphocytes and monocytes. J Infect Dis. 1995 Sep;172(3):665–671. [PubMed]
  • Horn CA, Washburn RG. Anticryptococcal activity of NK cell-enriched peripheral blood lymphocytes from human immunodeficiency virus-infected subjects: responses to interleukin-2, interferon-gamma, and interleukin-12. J Infect Dis. 1995 Oct;172(4):1023–1027. [PubMed]
  • Ibrahim AS, Filler SG, Ghannoum MA, Edwards JE., Jr Interferon-gamma protects endothelial cells from damage by Candida albicans. J Infect Dis. 1993 Jun;167(6):1467–1470. [PubMed]
  • Jouault T, Bernigaud A, Lepage G, Trinel PA, Poulain D. The Candida albicans phospholipomannan induces in vitro production of tumour necrosis factor-alpha from human and murine macrophages. Immunology. 1994 Oct;83(2):268–273. [PubMed]
  • Jouault T, Lepage G, Bernigaud A, Trinel PA, Fradin C, Wieruszeski JM, Strecker G, Poulain D. Beta-1,2-linked oligomannosides from Candida albicans act as signals for tumor necrosis factor alpha production. Infect Immun. 1995 Jun;63(6):2378–2381. [PMC free article] [PubMed]
  • Levitz SM. The ecology of Cryptococcus neoformans and the epidemiology of cryptococcosis. Rev Infect Dis. 1991 Nov-Dec;13(6):1163–1169. [PubMed]
  • Levitz SM. Macrophage-Cryptococcus interactions. Immunol Ser. 1994;60:533–543. [PubMed]
  • Levitz SM, DiBenedetto DJ. Differential stimulation of murine resident peritoneal cells by selectively opsonized encapsulated and acapsular Cryptococcus neoformans. Infect Immun. 1988 Oct;56(10):2544–2551. [PMC free article] [PubMed]
  • Levitz SM, Dupont MP. Phenotypic and functional characterization of human lymphocytes activated by interleukin-2 to directly inhibit growth of Cryptococcus neoformans in vitro. J Clin Invest. 1993 Apr;91(4):1490–1498. [PMC free article] [PubMed]
  • Levitz SM, Dupont MP, Smail EH. Direct activity of human T lymphocytes and natural killer cells against Cryptococcus neoformans. Infect Immun. 1994 Jan;62(1):194–202. [PMC free article] [PubMed]
  • Levitz SM, Lyman CA, Murata T, Sullivan JA, Mandell GL, Diamond RD. Cytosolic calcium changes in individual neutrophils stimulated by opsonized and unopsonized Candida albicans hyphae. Infect Immun. 1987 Nov;55(11):2783–2788. [PMC free article] [PubMed]
  • Levitz SM, Mathews HL, Murphy JW. Direct antimicrobial activity of T cells. Immunol Today. 1995 Aug;16(8):387–391. [PubMed]
  • Levitz SM, North EA, Dupont MP, Harrison TS. Mechanisms of inhibition of Cryptococcus neoformans by human lymphocytes. Infect Immun. 1995 Sep;63(9):3550–3554. [PMC free article] [PubMed]
  • Levitz SM, Tabuni A, Kornfeld H, Reardon CC, Golenbock DT. Production of tumor necrosis factor alpha in human leukocytes stimulated by Cryptococcus neoformans. Infect Immun. 1994 May;62(5):1975–1981. [PMC free article] [PubMed]
  • Maródi L, Schreiber S, Anderson DC, MacDermott RP, Korchak HM, Johnston RB., Jr Enhancement of macrophage candidacidal activity by interferon-gamma. Increased phagocytosis, killing, and calcium signal mediated by a decreased number of mannose receptors. J Clin Invest. 1993 Jun;91(6):2596–2601. [PMC free article] [PubMed]
  • Miller MF, Mitchell TG, Storkus WJ, Dawson JR. Human natural killer cells do not inhibit growth of Cryptococcus neoformans in the absence of antibody. Infect Immun. 1990 Mar;58(3):639–645. [PMC free article] [PubMed]
  • Murphy JW. Mechanisms of natural resistance to human pathogenic fungi. Annu Rev Microbiol. 1991;45:509–538. [PubMed]
  • Murphy JW, Hidore MR, Wong SC. Direct interactions of human lymphocytes with the yeast-like organism, Cryptococcus neoformans. J Clin Invest. 1993 Apr;91(4):1553–1566. [PMC free article] [PubMed]
  • Roilides E, Uhlig K, Venzon D, Pizzo PA, Walsh TJ. Neutrophil oxidative burst in response to blastoconidia and pseudohyphae of Candida albicans: augmentation by granulocyte colony-stimulating factor and interferon-gamma. J Infect Dis. 1992 Sep;166(3):668–673. [PubMed]
  • Shen F, Xu XL, Graf LH, Chong AS. CD45-cross-linking stimulates IFN-gamma production in NK cells. J Immunol. 1995 Jan 15;154(2):644–652. [PubMed]
  • Treseler CB, Maziarz RT, Levitz SM. Biological activity of interleukin-2 bound to Candida albicans. Infect Immun. 1992 Jan;60(1):183–188. [PMC free article] [PubMed]
  • Weiss A, Wiskocil RL, Stobo JD. The role of T3 surface molecules in the activation of human T cells: a two-stimulus requirement for IL 2 production reflects events occurring at a pre-translational level. J Immunol. 1984 Jul;133(1):123–128. [PubMed]
  • Ye J, Ortaldo JR, Conlon K, Winkler-Pickett R, Young HA. Cellular and molecular mechanisms of IFN-gamma production induced by IL-2 and IL-12 in a human NK cell line. J Leukoc Biol. 1995 Aug;58(2):225–233. [PubMed]
  • Zunino SJ, Hudig D. Interactions between human natural killer (NK) lymphocytes and yeast cells: human NK cells do not kill Candida albicans, although C. albicans blocks NK lysis of K562 cells. Infect Immun. 1988 Mar;56(3):564–569. [PMC free article] [PubMed]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)