Cytotoxic response persists in subjects treated for tuberculosis decades ago

BMC Infectious Diseases

Tamara Tuuminen¹  Benita Westerlund-Wikström³  Riitta Tuompo⁵  Liana Pusa⁴  Heikki Valleala⁵  Anu Kantele²  Pekka Koskivirta⁶  Laura E Savolainen⁶ 

[1] Eastern Finland Laboratory Centre Joint Authority Enterprise, Mikkeli, Finland;Institute of Clinical Medicine, Department of Medicine, University of Helsinki, Helsinki, Finland;Division of General Microbiology, Department of Biosciences, University of Helsinki, Helsinki, Finland;Länsi-Uusimaa Hospital, Tammisaari, Finland;Division of Rheumatology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland;Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, PL 21, Helsinki 00014, Finland

关键词: Memory T cells;    Perforin;    CD107a;    Granzyme B;    Immunodiagnostics;    CTLs;    Tuberculosis;   

Others  :  1145342
DOI  :  10.1186/1471-2334-13-573

 received in 2013-07-16, accepted in 2013-12-04,  发布年份 2013

【 摘 要 】

Background

Data exploring the potential use of effector molecules produced by cytotoxic T lymphocytes (CTLs) in the immunodiagnostics of tuberculosis (TB) are scarce. The present study focused a) to gain an insight into the discriminatory power of CTLs in patients with acute pulmonary or extra-pulmonary TB, or latent tuberculosis infection (LTBI); and b) to evaluate the influence of various anti-TB therapeutic schemes on the immunological profiles of residual CTLs.

Methods

Immunological signatures of antigen-specific CTLs were explored in patients with active pulmonary and extra-pulmonary TB, LTBI and in those treated for TB decades ago by using ELISPOT, intracellular flow cytometry and extracellular CD107a detection.

Results

No difference was seen between active TB, LTBI or any of those treated for TB in the ELISPOT analysis of antigen-specific Granzyme B (GrB), Perforin (Prf) and interferon-gamma (IFN-γ) producing lymphocytes, the FACS analysis of the intracellular expression of IFN-γ, or the surface expression of CD107a degranulation factor of both CD8⁺ and CD4⁺ antigen-specific T cell subsets. The effector memory (T_EM) phenotype proved predominant in the surface marker profiling both in active TB and LTBI. The proportion of the CD107a degranulation factor proved higher in the central memory (T_CM) than in the other cell subsets in all the study groups. Interestingly, functionally and phenotypically similar CTLs profiles were observed in active TB, LTBI and in all the three groups treated for TB.

Conclusion

The phenotypic and functional profiling of CTLs has a limited potential in the immunodiagnostics of active TB. Antigen-specific CTLs persist in patients treated for TB decades ago regardless of the efficacy of implemented and completed anti-TB therapy.

【 授权许可】

   
2013 Savolainen et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

【 参考文献 】

• [1]Centre for Disease Control and Prevention: Updated guidelines for using interferon-gamma release assays to detect Mycobacterium tuberculosis infection. United States: CDC; 2010. Available at: http://www.cdc.gov/mmwr/pdf/rr/rr5905.pdf webcite
• [2]European Centre for Disease Prevention and Control: Use of interferon-gamma release assays in support of TB diagnosis. Stockholm: EDCD; 2011. Available at: http://ecdc.europa.eu/en/publications/Publications/1103_GUI_IGRA.pdf webcite
• [3]Menzies D, Pai M, Comstock G: Meta-analysis: new tests for the diagnosis of latent tuberculosis infection: areas of uncertainty and recommendations for research. Ann Intern Med 2007, 146:340-354.
• [4]Tapaninen P, Korhonen A, Pusa L, Seppälä I, Tuuminen T: Effector memory T-cells dominate immune responses in tuberculosis treatment: antigen or bacteria persistence? Int J Tuberc Lung Dis 2010, 14:347-355.
• [5]McNerney R, Maeurer M, Abubakar I, Marais B, McHugh TD, Ford N, Weyer K, Lawn S, Mwaba P, Zijenah L, Hoelscher M, Cox H, Swaminathan S, Kim PS, Schito M, Harari A, Bates M, Schwank S, O’Grady J, Pletschette M, Ditui L, Atun R, Zumla A: Tuberculosis diagnostics and biomarkers: needs, challenges, recent advances opportunities. J Infect Dis 2012, 205:147-158.
• [6]Walzl G, Ronacher K, Hanekom W, Scriba TJ, Zumla A: Immunological biomarkers of tuberculosis. Nat Rev Immunol 2011, 11:343-354.
• [7]Young JM, Adetifa IMO, Ota MOC, Sutherland JS: Expanded polyfunctional T cell responses to Mycobacterial antigens in TB disease and contraction post-treatment. PLoS ONE 2010, 5:e11237.
• [8]Day CL, Abrahams DA, Lerumo L, Janse van Rensburg E, Stone L, O’rie T, Pienaar B, de Kock M, Kaplan G, Mahomed H, Dheda K, Hanekom WA: Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J Immunol 2011, 187:2222-2232.
• [9]Nemeth J, Winkler HM, Boeck L, Adegnika AA, Clement E, Mve TM, Kremsner PG, Winkler S: Specific cytokine patterns of pulmonary tuberculosis in Central Africa. Clin Immunol 2011, 138:50-59.
• [10]Adekambi T, Ibegbu CC, Kalokhe AS, Yu T, Ray SM, Rengarajan J: Distinct effector memory CD4+ T cell signatures in latent Mycobacterium tuberculosis infection, BCG vaccination and clinically resolved tuberculosis. PLoS ONE 2012, 7:e36046.
• [11]Lord SJ, Rajotte RV, Korbutt GS, Bleackley RC: Granzyme B: a natural born killer. Immunol Rev 2003, 193:31-38.
• [12]Barry M, Bleackley RC: Cytotoxic T lymphocytes: all roads lead to death. Nat Rev Immunol 2002, 2:401-409.
• [13]Lieberman J: The abcs of granule-mediated cytotoxicity: new weapons in the arsenal. Nat Rev Immunol 2003, 3:361-370.
• [14]Peters PJ, Borst J, Oorschot V, Fukuda M, Krähenbühl O, Tschopp J, Slot JW, Geuze HJ: Cytotoxic T lymphocyte granules are secretory lysosomes, containing both perforin and granzymes. Clin Exp Immunol 1991, 173:1099-1109.
• [15]Betts MR, Brenchley JM, Price DA, De Rosa SC, Douek DC, Roederer M, Koup RA: Sensitive and viable identification of antigen-specific CD8+ T cells by a flow cytometric assay for degranulation. J Immunol Methods 2003, 281:65-78.
• [16]Rininsland FH, Helms T, Asaad RJ, Boehm BO, Tary-Lehmann M: Granzyme B ELISPOT assay for ex vivo measurements of T cell immunity. J Immunol Methods 2000, 240:143-155.
• [17]Zuber B, Levitsky V, Jonsson G, Paulie S, Samarina A, Grundstrom S, Metkar S, Norell H, Callender GG, Froelich C, Ahlborg N: Detection of human perforin by ELISpot and ELISA: ex vivo identification of virus-specific cells. J Immunol Methods 2005, 302:13-25.
• [18]Franken LMC, Hiemstra HS, van Meijgaarden KE, Subronto Y, den Hartigh J, Ottenhoff THM, Drijfhout W: Purification of His-tagged proteins by immobilized chelate affinity chromatography: the benefits from the use of organic solvent. Protein Exper Purif 2000, 18:95-99.
• [19]Tuuminen T, Sorva S, Liippo K, Vasankari T, Soini H, Eriksen-Neuman B, Miettinen A, Seppälä IJ: Feasibility of commercial interferon-gamma-based methods for the diagnosis of latent Mycobacterium tuberculosis infection in Finland, a country of low incidence and high bacille Calmette-Guerin vaccination coverage. Clin Microbiol Infect 2007, 13:836-838.
• [20]Caccamo N, Guggino G, Meraviglia S, Gelsomino G, Di Carlo P, Titone L, Bocchino M, Galati D, Matarese A, Nouta J, Klein MR, Salerno A, Sanduzzi A, Dieli F, Ottenhoff TH: Analysis of Mycobacterium tuberculosis-specific CD8 T-cells in patients with active tuberculosis and in individuals with latent infection. PLoS ONE 2009, 4:e5528.
• [21]Barry CE 3rd, Boshoff HI, Dartois V, Dick T, Ehrt S, Flynn J, Schnappinger D, Wilkinson RJ, Young D: The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 2009, 7:845-855.
• [22]Caccamo N, Meraviglia S, La Mendola C, Guggino G, Dieli F, Salerno A: Phenotypical and functional analysis of memory and effector human CD8 T cells specific for mycobacterial antigens. J Immunol 2006, 177:1780-1785.
• [23]Soares AP, Scriba TJ, Joseph S, Harbacheuski R, Murray RA, Gelderbloem SJ, Hawkridge A, Hussey GD, Maecker H, Kaplan G, Hanekom WA: Bacillus Calmette-Guérin vaccination of human newborns induces T cells with complex cytokine and phenotype profiles. J Immunol 2008, 5:3569-3577.
• [24]Axelsson-Robertson R, Loxton AG, Walzl G, Ehlers MM, Kock MM, Zumla A, Maeurer M: A broad profile of co-dominant epitopes shapes the peripheral Mycobacterium tuberculosis specific CD8+ T-cell immune response in South African patients with active tuberculosis. PLoS ONE 2013, 8:e58309.
• [25]Rock MT, Yoder SM, Wright PF, Talbot TR, Edwards KM, Crowe JE Jr: Differential regulation of granzyme and perforin in effector and memory T cells following smallpox immunization. J Immunol 2005, 174:3757-3764.
• [26]Takata H, Takiguchi M: Three memory subsets of human CD8+ T cells differently expressing three cytolytic effector molecules. J Immunol 2006, 177:4330-4340.
• [27]Goletti D, Butera O, Vanini V, Lauria FN, Lange C, Franken KL, Angeletti C, Ottenhoff TH, Girardi E: Response to Rv2628 latency antigen associates with cured tuberculosis and remote infection. Eur Respir J 2010, 36:135-142.
• [28]Kumar MM, Raja A: Cytotoxicity responses to selected ESAT-6 and CFP-10 peptides in tuberculosis. Cell Immunol 2010, 265:146-155.
• [29]Kamath A, Woodworth JSM, Behar SM: Antigen-specific CD8+ T cells and the development of central memory during Mycobacterium tuberculosis infection. J Immunol 2006, 177:6361-6369.
• [30]De la Barrera SS, Finiasz M, Frias A, Aleman M, Barrionuevo P, Fink S, Franco MC: Specific lytic activity against mycobacterial antigens is inversely correlated with the severity of tuberculosis. Clin Exp Immunol 2003, 132:450-461.
• [31]Canaday DH, Wilkinson RJ, Li Q, Harding CV, Silver RF, Boom WH: CD4(+) and CD8(+) T cells kill intracellular Mycobacterium tuberculosis by a perforin and Fas/Fas ligand-independent mechanism. J Immunol 2001, 167:2734-2742.
• [32]Smith SM, Klein MR, Malin AS, Sillah J, Huygen K, Andersen P, McAdam KP, Dockrell HM: Human CD8(+) T cells specific for Mycobacterium tuberculosis secreted antigens in tuberculosis patients and healthy BCG-vaccinated controls in The Gambia. Infect Immun 2000, 68:7144-7148.
• [33]Pathan AA, Wilkinson KA, Wilkinson RJ, Latif M, McShane H, Pasvol G, Hill AV, Lalvani A: High frequencies of circulating IFN-γ-secreting CD8 cytotoxic T cells specific for a novel MHC class I-restricted Mycobacterium tuberculosis epitope in M. tuberculosis-infected subjects. Eur J Immunol 2000, 30:2713-2721.
• [34]Wherry EJ: T cell exhaustion. Nat Immunol 2011, 12:492-499.
• [35]Virgin HW, Wherry EJ, Ahmed R: Redefining chronic viral infection. Cell 2009, 138:30-50.
• [36]O’Hara GA, Welten SP, Klenerman P, Arens R: Memory T cell inflation: understanding cause and effect. Trends Immunol 2012, 33:84-90.
• [37]Snyder CM, Cho KS, Bonnett EL, van Dommelen S, Shellam GR, Hill AB: Memory inflation during chronic viral infection is maintained by continuous production of short-lived, functional T cells. Immunity 2008, 29:650-659.
• [38]Meng Y, Harlin H, O’Keefe JP, Gajewski TF: Induction of cytotoxic granules in human memory CD8+ T cell subsets requires cell cycle progression. J Immunol 2006, 177:1981-1987.
• [39]Einarsdottir T, Lockhart E, Flynn JL: Cytotoxicity and secretion of gamma interferon are carried out by distinct CD8 T cells during Mycobacterium tuberculosis infection. Infect Immun 2009, 77:4621-4630.
• [40]Lazarevic V, Nolt D, Flynn JL: Long-term control of Mycobacterium tuberculosis infection is mediated by dynamic immune responses. J Immunol 2005, 175:1107-1117.
• [41]Wolint P, Betts MR, Koup RA, Oxenius A: Immediate cytotoxicity but not degranulation distinguishes effector and memory subsets of CD8+ T cells. J Exp Med 2004, 199:925-936.
• [42]Lawn SD, Zumla AI: Tuberculosis. Lancet 2011, 378:57-72.
• [43]Ramakrihnan L: Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol 2012, 12:352-356.
• [44]Hershkovitz I, Donoghue HD, Minnikin DE, Besra GS, Lee OY, Gernaey AM, Galili E, Eshden V, Greenblatt CL, Lemma E, Bar-Gal GK, Spigelman M: Detection and molecular characterization of 9,000-year-old Mycobacterium tuberculosis from a Neolithic settlement in the Eastern Mediterranean. PLoS ONE 2008, 10:e3426.
• [45]Okada H, Kuhn C, Feillet H, Bach J-F: The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clin Exp Immunol 2010, 160:1-9.
• [46]Wold AE: The hygiene hypothesis revised: is the rising frequency of allergy due to changes in the intestinal flora? Allergy 1998, 53:20-25.
• [47]WHO: Fact sheet, tuberculosis. 2012. Available at: http://www.who.int/mediacentre/factsheets/fs104/en/index.html webcite
• [48]Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M, Diamond MS, Miller VL, Virgin HW 4th: Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 2007, 447:326-329.