Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization
The characteristic feature of Mycobacterium tuberculosis (Mtb) infection is the formation of lesions, which are organized structures of immune cells in the lungs called granulomas, which contain the bacteria. When the granuloma functions effectively, it can kill the bacteria. T cells (a type of immune cell, also present in granulomas) are known to play an important role in control of tuberculosis. However, functions of T cells at individual granuloma levels are unknown. Here, we studied the functional characteristics of T cells, which are defined by the production of chemical messengers (cytokines) at the granuloma level in a non-human primate model. We compared the relationship between cytokine response and the number of bacteria (Mtb) in each granuloma. Each granuloma was found to be unique, suggesting different types exist within an animal. Only a small proportion of T cells produced any cytokine, but different types of cytokines were observed within each granuloma. A balance between different types of cytokine was associated with more killing of bacteria in granulomas. Understanding how to improve the T cell responses to obtain killing of bacteria in the granuloma will be important for vaccine development.
Vyšlo v časopise:
Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization. PLoS Pathog 11(1): e32767. doi:10.1371/journal.ppat.1004603
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.ppat.1004603
Souhrn
The characteristic feature of Mycobacterium tuberculosis (Mtb) infection is the formation of lesions, which are organized structures of immune cells in the lungs called granulomas, which contain the bacteria. When the granuloma functions effectively, it can kill the bacteria. T cells (a type of immune cell, also present in granulomas) are known to play an important role in control of tuberculosis. However, functions of T cells at individual granuloma levels are unknown. Here, we studied the functional characteristics of T cells, which are defined by the production of chemical messengers (cytokines) at the granuloma level in a non-human primate model. We compared the relationship between cytokine response and the number of bacteria (Mtb) in each granuloma. Each granuloma was found to be unique, suggesting different types exist within an animal. Only a small proportion of T cells produced any cytokine, but different types of cytokines were observed within each granuloma. A balance between different types of cytokine was associated with more killing of bacteria in granulomas. Understanding how to improve the T cell responses to obtain killing of bacteria in the granuloma will be important for vaccine development.
Zdroje
1. Glaziou P, Falzon D, Floyd K, Raviglione M (2013) Global epidemiology of tuberculosis. Semin Respir Crit Care Med 34: 3–16. doi: 10.1055/s-0032-1333467 23460002
2. Lin PL, Ford CB, Coleman MT, Myers AJ, Gawande R, et al. (2014) Sterilization of granulomas is common in active and latent tuberculosis despite within-host variability in bacterial killing. Nat Med 20: 75–79. doi: 10.1038/nm.3412 24336248
3. Mattila JT, Ojo OO, Kepka-Lenhart D, Marino S, Kim JH, et al. (2013) Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms. J Immunol 191: 773–784. doi: 10.4049/jimmunol.1300113 23749634
4. Flynn JL, Chan J, Lin PL (2011) Macrophages and control of granulomatous inflammation in tuberculosis. Mucosal Immunol 4: 271–278. doi: 10.1038/mi.2011.14 21430653
5. Phuah JY, Mattila JT, Lin PL, Flynn JL (2012) Activated B cells in the granulomas of nonhuman primates infected with Mycobacterium tuberculosis. Am J Pathol 181: 508–514. doi: 10.1016/j.ajpath.2012.05.009 22721647
6. Ramakrishnan L (2012) Revisiting the role of the granuloma in tuberculosis. Nat Rev Immunol 12: 352–366. doi: 10.1038/nri3211 22517424
7. Torrado E, Cooper AM (2010) IL-17 and Th17 cells in tuberculosis. Cytokine Growth Factor Rev 21: 455–462. doi: 10.1016/j.cytogfr.2010.10.004 21075039
8. Cooper AM, Flynn JL (1995) The protective immune response to Mycobacterium tuberculosis. Curr Opin Immunol 7: 512–516. doi: 10.1016/0952-7915(95)80096-4 7495515
9. Flynn JL (2004) Immunology of tuberculosis and implications in vaccine development. Tuberculosis (Edinb) 84: 93–101. doi: 10.1016/j.tube.2003.08.010 14670350
10. Flynn JL, Chan J (2001) Immunology of tuberculosis. Annu Rev Immunol 19: 93–129. doi: 10.1146/annurev.immunol.19.1.93 11244032
11. Flynn JL, Chan J (2005) What’s good for the host is good for the bug. Trends Microbiol 13: 98–102. doi: 10.1016/j.tim.2005.01.005 15737727
12. O’Garra A, Redford PS, McNab FW, Bloom CI, Wilkinson RJ, et al. (2013) The immune response in tuberculosis. Annu Rev Immunol 31: 475–527. doi: 10.1146/annurev-immunol-032712-095939 23516984
13. Algood HM, Lin PL, Flynn JL (2005) Tumor necrosis factor and chemokine interactions in the formation and maintenance of granulomas in tuberculosis. Clin Infect Dis 41 Suppl 3: S189–193. doi: 10.1086/429994 15983898
14. Flynn JL, Ernst JD (2000) Immune responses in tuberculosis. Curr Opin Immunol 12: 432–436. doi: 10.1016/S0952-7915(00)00116-3 10899019
15. Green AM, Mattila JT, Bigbee CL, Bongers KS, Lin PL, et al. (2010) CD4(+) regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection. J Infect Dis 202: 533–541. doi: 10.1086/654896 20617900
16. Lee J, Kornfeld H (2010) Interferon-gamma Regulates the Death of M. tuberculosis-Infected Macrophages. J Cell Death 3: 1–11. 21072140
17. Lin PL, Myers A, Smith L, Bigbee C, Bigbee M, et al. (2010) Tumor necrosis factor neutralization results in disseminated disease in acute and latent Mycobacterium tuberculosis infection with normal granuloma structure in a cynomolgus macaque model. Arthritis Rheum 62: 340–350. doi: 10.1002/art.27271 20112395
18. Lin PL, Plessner HL, Voitenok NN, Flynn JL (2007) Tumor necrosis factor and tuberculosis. J Investig Dermatol Symp Proc 12: 22–25. doi: 10.1038/sj.jidsymp.5650027 17502865
19. Quesniaux VF, Jacobs M, Allie N, Grivennikov S, Nedospasov SA, et al. (2010) TNF in host resistance to tuberculosis infection. Curr Dir Autoimmun 11: 157–179. doi: 10.1159/000289204 20173394
20. Green AM, Difazio R, Flynn JL (2013) IFN-gamma from CD4 T cells is essential for host survival and enhances CD8 T cell function during Mycobacterium tuberculosis infection. J Immunol 190: 270–277. doi: 10.4049/jimmunol.1200061 23233724
21. Marino S, Myers A, Flynn JL, Kirschner DE (2010) TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: a next-generation two-compartmental model. J Theor Biol 265: 586–598. doi: 10.1016/j.jtbi.2010.05.012 20510249
22. Flynn JL, Bloom BR (1996) Role of T1 and T2 cytokines in the response to Mycobacterium tuberculosis. Ann N Y Acad Sci 795: 137–146. doi: 10.1111/j.1749-6632.1996.tb52662.x 8958924
23. Tsai MC, Chakravarty S, Zhu G, Xu J, Tanaka K, et al. (2006) Characterization of the tuberculous granuloma in murine and human lungs: cellular composition and relative tissue oxygen tension. Cell Microbiol 8: 218–232. doi: 10.1111/j.1462-5822.2005.00612.x 16441433
24. Lin PL, Pawar S, Myers A, Pegu A, Fuhrman C, et al. (2006) Early events in Mycobacterium tuberculosis infection in cynomolgus macaques. Infect Immun 74: 3790–3803. doi: 10.1128/IAI.00064-06 16790751
25. Lin PL, Rodgers M, Smith L, Bigbee M, Myers A, et al. (2009) Quantitative comparison of active and latent tuberculosis in the cynomolgus macaque model. Infect Immun 77: 4631–4642. doi: 10.1128/IAI.00592-09 19620341
26. Capuano SV 3rd, Croix DA, Pawar S, Zinovik A, Myers A, et al. (2003) Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection. Infect Immun 71: 5831–5844. doi: 10.1128/IAI.71.10.5831-5844.2003 14500505
27. Via LE, Lin PL, Ray SM, Carrillo J, Allen SS, et al. (2008) Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. Infect Immun 76: 2333–2340. doi: 10.1128/IAI.01515-07 18347040
28. Canetti G (1955) The Tubercule Bacillus. Springer Publishing Co, Inc, New York, NY.
29. Lin PL, Coleman T, Carney JP, Lopresti BJ, Tomko J, et al. (2013) Radiologic responses in cynomolgous macaques for assessing tuberculosis chemotherapy regimens. Antimicrob Agents Chemother 57: 4237–4244. 23796926
30. Coleman MT, Maiello P, Tomko J, Frye LJ, Fillmore D, et al. (2014) Early Changes by 18Fluorodeoxyglucose Positron Emission Tomography Coregistered with Computed Tomography Predict Outcome after Mycobacterium tuberculosis Infection in Cynomolgus Macaques. Infect Immun 82: 2400–2404. doi: 10.1128/IAI.01599-13 24664509
31. Brighenti S, Andersson J (2012) Local immune responses in human tuberculosis: learning from the site of infection. J Infect Dis 205 Suppl 2: S316–324. doi: 10.1093/infdis/jis043 22448014
32. Millington KA, Innes JA, Hackforth S, Hinks TS, Deeks JJ, et al. (2007) Dynamic relationship between IFN-gamma and IL-2 profile of Mycobacterium tuberculosis-specific T cells and antigen load. J Immunol 178: 5217–5226. 17404305
33. Khader SA, Gopal R (2010) IL-17 in protective immunity to intracellular pathogens. Virulence 1: 423–427. doi: 10.4161/viru.1.5.12862 21178483
34. Khader SA, Bell GK, Pearl JE, Fountain JJ, Rangel-Moreno J, et al. (2007) IL-23 and IL-17 in the establishment of protective pulmonary CD4+ T cell responses after vaccination and during Mycobacterium tuberculosis challenge. Nat Immunol 8: 369–377. doi: 10.1038/ni1449 17351619
35. Redford PS, Murray PJ, O’Garra A (2011) The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol 4: 261–270. doi: 10.1038/mi.2011.7 21451501
36. Cilfone NA, Perry CR, Kirschner DE, Linderman JJ (2013) Multi-scale modeling predicts a balance of tumor necrosis factor-alpha and interleukin-10 controls the granuloma environment during Mycobacterium tuberculosis infection. PLoS One 8: e68680. doi: 10.1371/journal.pone.0068680 23869227
37. Marino S, Kirschner DE (2004) The human immune response to Mycobacterium tuberculosis in lung and lymph node. J Theor Biol 227: 463–486. doi: 10.1016/j.jtbi.2003.11.023 15038983
38. Wigginton JE, Kirschner D (2001) A model to predict cell-mediated immune regulatory mechanisms during human infection with Mycobacterium tuberculosis. J Immunol 166: 1951–1967. 11160244
39. Egen JG, Rothfuchs AG, Feng CG, Horwitz MA, Sher A, et al. (2011) Intravital imaging reveals limited antigen presentation and T cell effector function in mycobacterial granulomas. Immunity 34: 807–819. doi: 10.1016/j.immuni.2011.03.022 21596592
40. Fenhalls G, Wong A, Bezuidenhout J, van Helden P, Bardin P, et al. (2000) In situ production of gamma interferon, interleukin-4, and tumor necrosis factor alpha mRNA in human lung tuberculous granulomas. Infect Immun 68: 2827–2836. doi: 10.1128/IAI.68.5.2827-2836.2000 10768979
41. Theron G, Peter J, Lenders L, van Zyl-Smit R, Meldau R, et al. (2012) Correlation of mycobacterium tuberculosis specific and non-specific quantitative Th1 T-cell responses with bacillary load in a high burden setting. PLoS One 7: e37436. doi: 10.1371/journal.pone.0037436 22629395
42. Beveridge NE, Price DA, Casazza JP, Pathan AA, Sander CR, et al. (2007) Immunisation with BCG and recombinant MVA85A induces long-lasting, polyfunctional Mycobacterium tuberculosis-specific CD4+ memory T lymphocyte populations. Eur J Immunol 37: 3089–3100. doi: 10.1002/eji.200737504 17948267
43. Scriba TJ, Tameris M, Mansoor N, Smit E, van der Merwe L, et al. (2010) Modified vaccinia Ankara-expressing Ag85A, a novel tuberculosis vaccine, is safe in adolescents and children, and induces polyfunctional CD4+ T cells. Eur J Immunol 40: 279–290. doi: 10.1002/eji.200939754 20017188
44. Wilkinson KA, Wilkinson RJ (2010) Polyfunctional T cells in human tuberculosis. Eur J Immunol 40: 2139–2142. doi: 10.1002/eji.201040731 20853500
45. Forbes EK, Sander C, Ronan EO, McShane H, Hill AV, et al. (2008) Multifunctional, high-level cytokine-producing Th1 cells in the lung, but not spleen, correlate with protection against Mycobacterium tuberculosis aerosol challenge in mice. J Immunol 181: 4955–4964. 18802099
46. Darrah PA, Patel DT, De Luca PM, Lindsay RW, Davey DF, et al. (2007) Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major. Nat Med 13: 843–850. doi: 10.1038/nm1592 17558415
47. Sutherland JS, Adetifa IM, Hill PC, Adegbola RA, Ota MO (2009) Pattern and diversity of cytokine production differentiates between Mycobacterium tuberculosis infection and disease. Eur J Immunol 39: 723–729. doi: 10.1002/eji.200838693 19224636
48. Caccamo N, Guggino G, Joosten SA, Gelsomino G, Di Carlo P, et al. (2010) Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection. Eur J Immunol 40: 2211–2220. doi: 10.1002/eji.201040455 20540114
49. Peters A, Lee Y, Kuchroo VK (2011) The many faces of Th17 cells. Curr Opin Immunol 23: 702–706. doi: 10.1016/j.coi.2011.08.007 21899997
50. Korn T, Bettelli E, Oukka M, Kuchroo VK (2009) IL-17 and Th17 Cells. Annu Rev Immunol 27: 485–517. doi: 10.1146/annurev.immunol.021908.132710 19132915
51. Via LE, Weiner DM, Schimel D, Lin PL, Dayao E, et al. (2013) Differential virulence and disease progression following Mycobacterium tuberculosis complex infection of the common marmoset (Callithrix jacchus). Infect Immun 81: 2909–2919. doi: 10.1128/IAI.00632-13 23716617
52. Barry CE 3rd, Boshoff HI, Dartois V, Dick T, Ehrt S, et al. (2009) The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nat Rev Microbiol 7: 845–855. doi: 10.1038/nrmicro2236 19855401
53. JoAnne F, Edwin K (2010) Pulmonary Tuberculosis in Monkeys. A Color Atlas of Comparative Pathology of Pulmonary Tuberculosis: CRC Press. pp. 83–105.
54. Gideon HP, Flynn JL (2011) Latent tuberculosis: what the host “sees”? Immunol Res 50: 202–212. doi: 10.1007/s12026-011-8229-7 21717066
55. Lin PL, Flynn JL (2010) Understanding latent tuberculosis: a moving target. J Immunol 185: 15–22. doi: 10.4049/jimmunol.0903856 20562268
56. Peters W, Ernst JD (2003) Mechanisms of cell recruitment in the immune response to Mycobacterium tuberculosis. Microbes Infect 5: 151–158. doi: 10.1016/S1286-4579(02)00082-5 12650773
57. Wilkinson KA, Wilkinson RJ, Pathan A, Ewer K, Prakash M, et al. (2005) Ex vivo characterization of early secretory antigenic target 6-specific T cells at sites of active disease in pleural tuberculosis. Clin Infect Dis 40: 184–187. doi: 10.1086/426139 15614710
58. Jafari C, Ernst M, Strassburg A, Greinert U, Kalsdorf B, et al. (2008) Local immunodiagnosis of pulmonary tuberculosis by enzyme-linked immunospot. Eur Respir J 31: 261–265. doi: 10.1183/09031936.00096707 17989118
59. Jafari C, Thijsen S, Sotgiu G, Goletti D, Dominguez Benitez JA, et al. (2009) Bronchoalveolar lavage enzyme-linked immunospot for a rapid diagnosis of tuberculosis: a Tuberculosis Network European Trialsgroup study. Am J Respir Crit Care Med 180: 666–673. doi: 10.1164/rccm.200904-0557OC 19590020
60. Fuller CL, Flynn JL, Reinhart TA (2003) In situ study of abundant expression of proinflammatory chemokines and cytokines in pulmonary granulomas that develop in cynomolgus macaques experimentally infected with Mycobacterium tuberculosis. Infect Immun 71: 7023–7034. doi: 10.1128/IAI.71.12.7023-7034.2003 14638792
61. Harding CV, Boom WH (2010) Regulation of antigen presentation by Mycobacterium tuberculosis: a role for Toll-like receptors. Nat Rev Microbiol 8: 296–307. doi: 10.1038/nrmicro2321 20234378
62. Chang ST, Linderman JJ, Kirschner DE (2005) Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages. Proc Natl Acad Sci U S A 102: 4530–4535. doi: 10.1073/pnas.0500362102 15767567
63. Nikitina IY, Kondratuk NA, Kosmiadi GA, Amansahedov RB, Vasilyeva IA, et al. (2012) Mtb-specific CD27low CD4 T cells as markers of lung tissue destruction during pulmonary tuberculosis in humans. PLoS One 7: e43733. doi: 10.1371/journal.pone.0043733 22937086
64. Qiu Z, Zhang M, Zhu Y, Zheng F, Lu P, et al. (2012) Multifunctional CD4 T cell responses in patients with active tuberculosis. Sci Rep 2: 216. doi: 10.1038/srep00216 22355730
65. Mattila JT, Diedrich CR, Lin PL, Phuah J, Flynn JL (2011) Simian immunodeficiency virus-induced changes in T cell cytokine responses in cynomolgus macaques with latent Mycobacterium tuberculosis infection are associated with timing of reactivation. J Immunol 186: 3527–3537. doi: 10.4049/jimmunol.1003773 21317393
66. Tameris M, McShane H, McClain JB, Landry B, Lockhart S, et al. (2013) Lessons learnt from the first efficacy trial of a new infant tuberculosis vaccine since BCG. Tuberculosis (Edinb) 93: 143–149. doi: 10.1016/j.tube.2013.01.003 23410889
67. Tameris MD, Hatherill M, Landry BS, Scriba TJ, Snowden MA, et al. (2013) Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 381: 1021–1028. doi: 10.1016/S0140-6736(13)60177-4 23391465
68. Wallis RS, Kim P, Cole S, Hanna D, Andrade BB, et al. (2013) Tuberculosis biomarkers discovery: developments, needs, and challenges. Lancet Infect Dis 13: 362–372. doi: 10.1016/S1473-3099(13)70034-3 23531389
69. Lin PL, Coleman T, Carney JP, Lopresti BJ, Tomko J, et al. (2013) Radiologic responses in cynomolgous macaques for assessing tuberculosis chemotherapy regimens. Antimicrob Agents Chemother.
70. Pawar SN, Mattila JT, Sturgeon TJ, Lin PL, Narayan O, et al. (2008) Comparison of the effects of pathogenic simian human immunodeficiency virus strains SHIV-89.6P and SHIV-KU2 in cynomolgus macaques. AIDS Res Hum Retroviruses 24: 643–654. doi: 10.1089/aid.2007.0238 18366326
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Hygiena a epidemiológia Infekčné lekárstvo LaboratóriumČlánok vyšiel v časopise
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