Skip to main content

Advertisement

SpringerLink
Log in

Human yeast-specific CD8 T lymphocytes show a nonclassical effector molecule profile

  • Original Investigation
  • Published:
Medical Microbiology and Immunology Aims and scope Submit manuscript

Abstract

Pathogenic yeast and fungi represent a major group of human pathogens. The consequences of infections are diverse and range from local, clinically uncomplicated mycosis of the skin to systemic, life-threatening sepsis. Despite extensive MHC class I-restricted frequencies of yeast-specific CD8 T lymphocytes in healthy individuals and the essential role of the cell-mediated immunity in controlling infections, the characteristics and defense mechanisms of antifungal effector cells are still unclear. Here, we describe the direct analysis of yeast-specific CD8 T lymphocytes in whole blood from healthy individuals. They show a unique, nonclassical phenotype expressing granulysin and granzyme K in lytic granules instead of the major effector molecules perforin and granzyme B. After stimulation in whole blood, yeast-specific CD8 T cells degranulated and, upon cultivation in the presence of IL-2, their granula were refilled with granulysin rather than with perforin and granzyme B. Moreover, yeast-specific stimulation through dendritic cells but not by yeast cells alone led to degranulation of the effector cells. As granulysin is the only effector molecule in lytic granules known to have antifungal properties, our data suggest yeast-specific CD8 T cells to be a nonclassical effector population whose antimicrobial effector machinery seems to be tailor-made for the efficient elimination of fungi as pathogens.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Pfaller MA, Moet GJ, Messer SA, Jones RN, Castanheira M (2010) Candida bloodstream infections: comparison of species distributions and antifungal resistance patterns in community-onset and nosocomial isolates in the SENTRY antimicrobial surveillance program, 2008–2009. Antimicrob Agents Chemother 55:561–566

    Article  PubMed  Google Scholar 

  2. Shoham S, Levitz SM (2005) The immune response to fungal infections. Br J Haematol 129:569–582

    Article  PubMed  Google Scholar 

  3. Richards MJ, Edwards JR, Culver DH, Gaynes RP (1999) Nosocomial infections in medical intensive care units in the United States. National nosocomial infections surveillance system. Crit Care Med 27:887–892

    Article  PubMed  CAS  Google Scholar 

  4. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP (1989) Risk factors for hospital-acquired candidemia. A matched case-control study. Arch Intern Med 149:2349–2353

    Article  PubMed  CAS  Google Scholar 

  5. Romani L (2004) Immunity to fungal infections. Nat Rev Immunol 4:1–23

    Article  PubMed  Google Scholar 

  6. Sohn K, Urban C, Brunner H, Rupp S (2003) EFG1 is a major regulator of cell wall dynamics in Candida albicans as revealed by DNA microarrays. Mol Microbiol 47:89–102

    Article  PubMed  CAS  Google Scholar 

  7. d’Ostiani CF, Del Sero G, Bacci A, Montagnoli C, Spreca A, Mencacci A, Ricciardi-Castagnoli P, Romani L (2000) Dendritic cells discriminate between yeasts and hyphae of the fungus Candida albicans. Implications for initiation of T helper cell immunity in vitro and in vivo. J Exp Med 191:1661–1674

    Google Scholar 

  8. Lorenz MC, Bender JA, Fink GR (2004) Transcriptional response of Candida albicans upon internalization by macrophages. Eukaryot Cell 3:1076–1087

    Article  PubMed  CAS  Google Scholar 

  9. Cutler JE, Deepe GS Jr, Klein BS (2007) Advances in combating fungal diseases: vaccines on the threshold. Nat Rev Microbiol 5:13–28

    Article  PubMed  CAS  Google Scholar 

  10. Mukherjee J, Nussbaum G, Scharff MD, Casadevall A (1995) Protective and nonprotective monoclonal antibodies to Cryptococcus neoformans originating from one B cell. J Exp Med 181:405–409

    Article  PubMed  CAS  Google Scholar 

  11. Romani L, Puccetti P, Bistoni F (1996) Biological role of Th cell subsets in candidiasis. Chem Immunol 63:115–137

    Article  PubMed  CAS  Google Scholar 

  12. Lopez-Ribot JL, Casanova M, Murgui A, Martinez JP (2004) Antibody response to Candida albicans cell wall antigens. FEMS Immunol Med Microbiol 41:187–196

    Article  PubMed  CAS  Google Scholar 

  13. Matthews R, Burnie J (2001) Antifungal antibodies: a new approach to the treatment of systemic candidiasis. Curr Opin Investig Drugs 2:472–476

    PubMed  CAS  Google Scholar 

  14. Levitz SM (1992) Overview of host defenses in fungal infections. Clin Infect Dis 14(Suppl 1):S37–S42

    Google Scholar 

  15. Romani L, Howard DH (1995) Mechanisms of resistance to fungal infections. Curr Opin Immunol 7:517–523

    Article  PubMed  CAS  Google Scholar 

  16. Huffnagle GB, Deepe GS (2003) Innate and adaptive determinants of host susceptibility to medically important fungi. Curr Opin Microbiol 6:344–350

    Article  PubMed  Google Scholar 

  17. Decken K, Kohler G, Palmer-Lehmann K, Wunderlin A, Mattner F, Magram J, Gately MK, Alber G (1998) Interleukin-12 is essential for a protective Th1 response in mice infected with Cryptococcus neoformans. Infect Immun 66:4994–5000

    PubMed  CAS  Google Scholar 

  18. Acosta-Rodriguez EV, Rivino L, Geginat J, Jarrossay D, Gattorno M, Lanzavecchia A, Sallusto F, Napolitani G (2007) Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells. Nat Immunol 8:639–646

    Article  PubMed  CAS  Google Scholar 

  19. Heintel T, Breinig F, Schmitt MJ, Meyerhans A (2003) Extensive MHC class I-restricted CD8 T lymphocyte responses against various yeast genera in humans. FEMS Immunol Med Microbiol 39:279–286

    Article  PubMed  CAS  Google Scholar 

  20. Barry M, Bleackley RC (2002) Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2:401–409

    PubMed  CAS  Google Scholar 

  21. Lieberman J (2003) The ABCs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol 3:361–370

    Article  PubMed  CAS  Google Scholar 

  22. Griffiths GM (1995) The cell biology of CTL killing. Curr Opin Immunol 7:343–348

    Article  PubMed  CAS  Google Scholar 

  23. Harari A, Enders FB, Cellerai C, Bart PA, Pantaleo G (2009) Distinct profiles of cytotoxic granules in memory CD8 T cells correlate with function, differentiation stage, and antigen exposure. J Virol 83:2862–2871

    Article  PubMed  CAS  Google Scholar 

  24. Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2:735–747

    Article  PubMed  CAS  Google Scholar 

  25. Zhao T, Zhang H, Guo Y, Fan Z (2007) Granzyme K directly processes bid to release cytochrome c and endonuclease G leading to mitochondria-dependent cell death. J Biol Chem 282:12104–12111

    Article  PubMed  CAS  Google Scholar 

  26. Ernst WA, Thoma-Uszynski S, Teitelbaum R, Ko C, Hanson DA, Clayberger C, Krensky AM, Leippe M, Bloom BR, Ganz T, Modlin RL (2000) Granulysin, a T cell product, kills bacteria by altering membrane permeability. J Immunol 165:7102–7108

    PubMed  CAS  Google Scholar 

  27. Ma LL, Spurrell JC, Wang JF, Neely GG, Epelman S, Krensky AM, Mody CH (2002) CD8 T cell-mediated killing of Cryptococcus neoformans requires granulysin and is dependent on CD4 T cells and IL-15. J Immunol 169:5787–5795

    PubMed  CAS  Google Scholar 

  28. Stenger S, Hanson DA, Teitelbaum R, Dewan P, Niazi KR, Froelich CJ, Ganz T, Thoma-Uszynski S, Melian A, Bogdan C, Porcelli SA, Bloom BR, Krensky AM, Modlin RL (1998) An antimicrobial activity of cytolytic T cells mediated by granulysin. Science 282:121–125

    Article  PubMed  CAS  Google Scholar 

  29. Huang LP, Lyu SC, Clayberger C, Krensky AM (2007) Granulysin-mediated tumour rejection in transgenic mice. J Immunol 178:77–84

    PubMed  CAS  Google Scholar 

  30. Hata A, Zerboni L, Sommer M, Kaspar AA, Clayberger C, Krensky AM, Arvin AM (2001) Granulysin blocks replication of varicella-zoster virus and triggers apoptosis of infected cells. Viral Immunol 14:125–133

    Article  PubMed  CAS  Google Scholar 

  31. Pardo J, Perez-Galan P, Gamen S, Marzo I, Monleon I, Kaspar AA, Susin SA, Kroemer G, Krensky AM, Naval J, Anel A (2001) A role of the mitochondrial apoptosis-inducing factor in granulysin-induced apoptosis. J Immunol 167:1222–1229

    PubMed  CAS  Google Scholar 

  32. Thoma-Uszynski S, Stenger S, Modlin RL (2000) CTL-mediated killing of intracellular Mycobacterium tuberculosis is independent of target cell nuclear apoptosis. J Immunol 165:5773–5779

    PubMed  CAS  Google Scholar 

  33. Breinig T, Sester M, Sester U, Meyerhans A (2006) Antigen-specific T cell responses: determination of their frequencies, homing properties, and effector functions in human whole blood. Methods 38:77–83

    Article  PubMed  CAS  Google Scholar 

  34. Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M, Koup RA (2003) Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 281:65–78

    Article  PubMed  CAS  Google Scholar 

  35. Schutz A, Scheller N, Breinig T, Meyerhans A (2006) The Autographa californica nuclear polyhedrosis virus AcNPV induces functional maturation of human monocyte-derived dendritic cells. Vaccine 24:7190–7196

    Article  PubMed  Google Scholar 

  36. Heintel T, Sester M, Rodriguez MM, Krieg C, Sester U, Wagner R, Pees HW, Gartner B, Maier R, Meyerhans A (2002) The fraction of perforin-expressing HIV-specific CD8 T cells is a marker for disease progression in HIV infection. Aids 16:1497–1501

    Article  PubMed  Google Scholar 

  37. Wang Z, Choice E, Kaspar A, Hanson D, Okada S, Lyu SC, Krensky AM, Clayberger C (2000) Bactericidal and tumoricidal activities of synthetic peptides derived from granulysin. J Immunol 165:1486–1490

    PubMed  CAS  Google Scholar 

  38. Pena SV, Hanson DA, Carr BA, Goralski TJ, Krensky AM (1997) Processing, subcellular localization, and function of 519 (granulysin), a human late T cell activation molecule with homology to small, lytic, granule proteins. J Immunol 158:2680–2688

    PubMed  CAS  Google Scholar 

  39. Zheng CF, Ma LL, Jones GJ, Gill MJ, Krensky AM, Kubes P, Mody CH (2007) Cytotoxic CD4+ T cells use granulysin to kill Cryptococcus neoformans, and activation of this pathway is defective in HIV patients. Blood 109:2049–2057

    Article  PubMed  CAS  Google Scholar 

  40. Beno DW, Stover AG, Mathews HL (1995) Growth inhibition of Candida albicans hyphae by CD8+ lymphocytes. J Immunol 154:5273–5281

    PubMed  CAS  Google Scholar 

  41. Levitz SM, North EA (1996) gamma Interferon gene expression and release in human lymphocytes directly activated by Cryptococcus neoformans and Candida albicans. Infect Immun 64:1595–1599

    PubMed  CAS  Google Scholar 

  42. Wuthrich M, Filutowicz HI, Warner T, Deepe GS Jr, Klein BS (2003) Vaccine immunity to pathogenic fungi overcomes the requirement for CD4 help in exogenous antigen presentation to CD8+ T cells: implications for vaccine development in immune-deficient hosts. J Exp Med 197:1405–1416

    Article  PubMed  CAS  Google Scholar 

  43. Lettau M, Schmidt H, Kabelitz D, Janssen O (2007) Secretory lysosomes and their cargo in T and NK cells. Immunol Lett 108:10–19

    Article  PubMed  CAS  Google Scholar 

  44. Zhou P, Freidag BL, Caldwell CC, Seder RA (2001) Perforin is required for primary immunity to Histoplasma capsulatum. J Immunol 166:1968–1974

    PubMed  CAS  Google Scholar 

  45. Fehniger TA, Cai SF, Cao X, Bredemeyer AJ, Presti RM, French AR, Ley TJ (2007) Acquisition of murine NK cell cytotoxicity requires the translation of a pre-existing pool of granzyme B and perforin mRNAs. Immunity 26:798–811

    Article  PubMed  CAS  Google Scholar 

  46. Glimcher LH, Townsend MJ, Sullivan BM, Lord GM (2004) Recent developments in the transcriptional regulation of cytolytic effector cells. Nat Rev Immunol 4:900–911

    Article  PubMed  CAS  Google Scholar 

  47. Intlekofer AM, Banerjee A, Takemoto N, Gordon SM, Dejong CS, Shin H, Hunter CA, Wherry EJ, Lindsten T, Reiner SL (2008) Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin. Science 321:408–411

    Article  PubMed  CAS  Google Scholar 

  48. Kaufmann SH (1988) CD8+ T lymphocytes in intracellular microbial infections. Immunol Today 9:168–174

    Article  PubMed  CAS  Google Scholar 

  49. Ludewig B, Bonilla WV, Dumrese T, Odermatt B, Zinkernagel RM, Hengartner H (2001) Perforin-independent regulation of dendritic cell homeostasis by CD8(+) T cells in vivo: implications for adaptive immunotherapy. Eur J Immunol 31:1772–1779

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The work was supported by the European Society of Clinical Microbiology and Infectious Diseases (ESCMID), the Forschungsförderung HOMFOR of the Saarland University to TB and the Spanish Ministry of Science and Innovation (SAF2010-21336) to AM. We thank Dr. Reinhard Maier for helpful discussions.

Author information

Author notes

  1. Tanja Breinig

    Present address: Computer Science, Saarland University, Building E1.3, 66123, Saarbrücken, Germany

Authors and Affiliations

  1. Junior Research Group for Virology/Immunology, Saarland University, 66421, Homburg, Germany

    Tanja Breinig

  2. Department of Virology, Saarland University, 66421, Homburg, Germany

    Tanja Breinig, Nicoletta Scheller, Birgit Glombitza & Andreas Meyerhans

  3. Molecular Virology Group, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003, Barcelona, Spain

    Nicoletta Scheller

  4. Department of Molecular and Cell Biology, Saarland University, 66123, Saarbrücken, Germany

    Frank Breinig

  5. ICREA Infection Biology Group, Department of Experimental and Health Sciences, University Pompeu Fabra, 08003, Barcelona, Spain

    Andreas Meyerhans

Authors
  1. Tanja Breinig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicoletta Scheller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Birgit Glombitza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Frank Breinig
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andreas Meyerhans
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tanja Breinig.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Breinig, T., Scheller, N., Glombitza, B. et al. Human yeast-specific CD8 T lymphocytes show a nonclassical effector molecule profile. Med Microbiol Immunol 201, 127–136 (2012). https://doi.org/10.1007/s00430-011-0213-2

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00430-011-0213-2

Keywords

Search

Navigation