T CELL EFFECTOR AND REGULATORY SUBSETS, DIFFERENTIATING BETWEEN ACTIVE AND LATENT MTB INFECTION
DOI:
https://doi.org/10.58395/pipd.v47i1.15Keywords:
LTBI, Th1/Th17, CD39 Treg, Th17TregAbstract
Last generation IFN gamma – based assays (IGRAs) evaluate bulk CD4 and CD8 T cell responses, and do not discriminate between latent and active Micobacterium tuberculosis (MTB) infection. The identification of biomarkers predicting the clinical course and specific therapy effect in latent MTB infection (LTBI) is a major contemporary challenge.
Using multicolor flow cytometry, we compared the levels of circulating CD8 and CD4 effector subsets, in relation to the levels of phenotypically defined regulatory subsets, in two groups of age- and sex-matched MTB-infected individuals: clinically and microbiologically confirmed ATB (n=15), and QFT+ stable LTBI (n=15).
As compared to LTBI subjects, ATB patients are characterized with decreased proportions of CD4 and CD8 CD45RO+CCR7- effectors (14.6% vs. 24%, and 28% vs. 40%, p <0.05 for both), decreased Th1 (10% vs. 16,5 %) and Th1/Th17 (12,5% vs. 21,5%) effector subsets. These changes are accompanied by a significantly increased share of induced (CD39+) FoxP3+CD4Treg (46% vs. 22.6%, p<0.05). The difference affected mostly the Th17-specific (CD39+CCR6+Treg) subset (10.5% vs 4.8%, p<0.05), which correlated inversely with the level of Th1/Th17 effectors (R= -0.5, p<0.05).
In conclusion, we describe a clear-cut distinction between the effector/ regulatory T subset balance in ATB and LTBI. The combined evaluation of Th17Treg and Th1/Th17 effectors in peripheral blood can be employed for MTB-infection monitoring.
ACKNOWLEDGMENTS: This work was supported by the Bulgarian National Science Fund (Research Grant ДН 13/1; 14.12.2017)
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GLOBAL TUBERCULOSIS REPORT 2018© World Health Organization 2018
Panajotov S, Velev V, Kostov T, Kantarjiev T, Levterova V. 79-year old man with wrist-joint tuberculosis – case report. Probl Infect Parasit Dis. 2003 31 (2):22.
Методическо указание за насочване, диагноза, проследяване и лечение на лицата с латентна туберкулозна инфекция. Министерство на здравеопазването, 2016. Утвърдено със Заповед № РД-01-74/10.03.2016 г. Налично на: http://www.mh.government.bg/
Andersen P, Doherty TM, Pai M, Weldingh K. The prognosis of latent tuberculosis: can disease be predicted? Trends Mol Med. 2007 May;13(5):175-82. DOI: https://doi.org/10.1016/j.molmed.2007.03.004
Pai M., Denkinger C., Kik S. et al Gamma Interferon Release Assays for Detection of Mycobacterium tuberculosis Infection. Clinical Microbiology Reviews. 2014; 27 (1): 3–20 DOI: https://doi.org/10.1128/CMR.00034-13
Yi L., Sasaki Y, Nagai H, et al. Evaluation of QuantiFERON-TB Gold Plus for Detection of Mycobacterium tuberculosis infection in Japan Scientific Reports. 2016; 6: Article number: 30617 DOI: https://doi.org/10.1038/srep30617
Petruccioli E, Vanini V, Chiacchio T, et al Analytical evaluation of QuantiFERON-Plus and QuantiFERON-Gold In-Tube assays in subjects with or without tuberculosis. Tuberculosis (Edinb) 2017; 106:38 – 43. DOI: https://doi.org/10.1016/j.tube.2017.06.002
Chien J, Chiang H, Lu M et al. QuantiFERON-TB Gold Plus Is a More Sensitive Screening Toolthan QuantiFERON-TB Gold In-Tube for Latent TuberculosisInfection among Older Adults in Long-Term Care Facilities Journalof Clinical Microbiology. 2018; 56: 8 e00427-18 DOI: https://doi.org/10.1128/JCM.00427-18
Nikolova M, Lelievre JD, Carriere M, et al. Regulatory T cells differentially modulate the maturation and apoptosis of human CD8+ T-cell subsets, Blood 2009 113:4556-4565; DOI: https://doi.org/10.1182/blood-2008-04-151407
Nikolova M, Wiedemann A, Lacabaratz C, Lévy Y. Deficiency of HIV-specific T cell responses: are the Treg guilty? Med Sci (Paris). 2017 Aug-Sep;33 (8-9):723-726. DOI: https://doi.org/10.1051/medsci/20173308012
Caza T, Landas S. Functional and Phenotypic Plasticity of CD4+ T Cell Subsets Biomed Res Int. 2015; 2015: 521957. DOI: https://doi.org/10.1155/2015/521957
Lindestam Arlehamn CS, Gerasimova A, Mele F,et al. Memory T Cells in Latent Mycobacterium tuberculosis Infection Are Directed against Three Antigenic Islands and Largely Contained in a CXCR3 + CCR6 + Th1 Subset. PLoS Pathog. 2013 9(1): e1003130 DOI: https://doi.org/10.1371/journal.ppat.1003130
Magid-Bernstein JR and Rohowsky-Kochan CM. Human CD39+ Treg Cells Express Th17-Associated Surface Markers and Suppress IL-17 via a Stat3-Dependent Mechanism J Interferon Cytokine Res. 2017 Apr 1; 37(4): 153–164 DOI: https://doi.org/10.1089/jir.2016.0071
Rangaka MX, Gideon HP, Wilkinson KA, et al. Interferon release does not add discriminatory value to smear-negative HIV-tuberculosis algorithms. Eur. Respir. J. 2012. 39:163–171. DOI: https://doi.org/10.1183/09031936.00058911
Metcalfe JZ, Cattamanchi A, Vittinghoff E, et al. Evaluation of quantitative IFN-gamma response for risk stratification of active tuberculosis suspects.. Am. J. Respir. Crit. Care Med. 2010.181:87–93. DOI: https://doi.org/10.1164/rccm.200906-0981OC
Ling DI, Pai M, Davids V, et al. Are interferon-gamma release assays useful for diagnosing active tuberculosis in a high-burden setting? Eur. Respir. J. 2011.38:649–656. DOI: https://doi.org/10.1183/09031936.00181610
Ling DI, Nicol M, Pai M, et al. Incremental value of T-SPOT. TB for diagnosis of active pulmonary tuberculosis in children in a high-burden setting: a multivariable analysis. Thorax 2013. 68:860–866. DOI: https://doi.org/10.1136/thoraxjnl-2012-203086
Lewinsohn DA, Heinzel AS, Gardner JM, et al. Mycobacterium tuberculosis–specific CD8+ T cells preferentially recognize heavily infected cells. Am J Respir Crit Care Med 2003; 168: 1346–1352. DOI: https://doi.org/10.1164/rccm.200306-837OC
Day CL, Abrahams DA, Lerumo L, et al. Functional capacity of Mycobacterium tuberculosis-specific T cell responses in humans is associated with mycobacterial load. J Immunol 2011; 187: 2222–2232 DOI: https://doi.org/10.4049/jimmunol.1101122
Rozot V, Vigano S, Mazza-Stalder J, et al. Mycobacterium tuberculosis-specific CD8+ T cells are functionally and phenotypically different between latent infection and active disease. Eur J Immunol 2013; 43: 1568–1577. DOI: https://doi.org/10.1002/eji.201243262
Barcellini L., Borroni E., Brown J., et al. First evaluation of QuantiFERON-TB Gold Plus performance in contact screening. European Respiratory Journal 2016 48: 1411-1419; DOI: https://doi.org/10.1183/13993003.00510-2016
Nikolova M, Markova R, Drenska R, et al. Antigen-specicfic CD4- and CD8-positive signatures in different phases of Mycobacterium tuberculosis infection. Diagn Microbiol Infect Dis 2013; 75: 277–281.Pollock KM et al. J Infect Dis. 2013;208(6):952-68 32. DOI: https://doi.org/10.1016/j.diagmicrobio.2012.11.023
Champagne P, Ogg GS, King AS, et al. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature. 2001; 410:106–111. [PubMed] [Google Scholar] DOI: https://doi.org/10.1038/35065118
Appay V, Nixon DF, Donahoe SM, et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med. 2000; 192:63–75. DOI: https://doi.org/10.1084/jem.192.1.63
Sacre K, Carcelain G, Cassoux N, et al. Repertoire, diversity, and differentiation of specific CD8 T cells are associated with immune protection against human cytomegalovirus disease. J Exp Med. 2005;201:1999–2010 DOI: https://doi.org/10.1084/jem.20042408
Nikolova M., Muhtarova M., Drenska R., et al Peripheral blood CD8 T cell responsein different phases of MTB infection. Comptes rendus de l’Acad́emie bulgare des Sciences 2013; 66, No 4 DOI: https://doi.org/10.7546/CR-2013-66-4-13101331-16
Mahnke YD, Brodie TM, Sallusto F, Roederer M, Lugli E. The who’s who of T-cell differentiation: human memory T-cell subsets. Eur J Immunol. 2013 Nov;43(11):2797-809. doi: 10.1002/eji. DOI: https://doi.org/10.1002/eji.201343751
Sutherland JS, Adetifa IM, Hill PC, Adegbola RA, Ota MO. Pattern and diversity of cytokine production differentiates between Mycobacterium tuberculosis infection and disease. Eur J Immunol. 2009 Mar;39(3):723-9. doi: 10.1002/eji.200838693. DOI: https://doi.org/10.1002/eji.200838693
Zhu J, Yamane H, Paul WE. Differentiation of effector CD4 T cell populations. Annu Rev Immunol (2010) 28:445–89. DOI: https://doi.org/10.1146/annurev-immunol-030409-101212
Palamaro L, Giardino G, Santamaria F, et al. Interleukin 12 receptor deficiency in a child with recurrent bronchopneumonia and very high IgE levels Ital J Pediatr. 2012; 38: 46. DOI: https://doi.org/10.1186/1824-7288-38-46
Lewinsohn DA, Lewinsohn DM, Scriba TJ. Polyfunctional CD4(+) T cells as targets for tuberculosis vaccination. Front Immunol. (2017) 8:1262. DOI: https://doi.org/10.3389/fimmu.2017.01262
Yoshida YO, Umemura M, Yahagi A, et al. Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. J Immunol 2010; 184:4414–4422. DOI: https://doi.org/10.4049/jimmunol.0903332
Shen H, Chen ZW. The crucial roles of Th17-related cytokines/signal pathways in M. tuberculosis infection. Cell Mol Immunol. 2018 Mar; 15(3):216-225. DOI: https://doi.org/10.1038/cmi.2017.128
Luo, J, Zhang, Mingxu, Yan, Baosong, Zhang, Kejun, Chen, Ming, & Deng, Shaoli. Imbalance of Th17 and Treg in peripheral blood mononuclear cells of active tuberculosis patients. Brazilian Journal of Infectious Diseases, 2017; 21(2),155-161 DOI: https://doi.org/10.1016/j.bjid.2016.10.011
García JRE, Serrano CJ, Enciso Moreno JA, et al.. Analysis of Th1, Th17 and regulatory T cells in tuberculosis case contacts Cell Immunol. 2014 May-Jun;289(1-2):167-73 DOI: https://doi.org/10.1016/j.cellimm.2014.03.010
Gosselin A, Monteiro P, Chomont N, Peripheral blood CCR4+CCR6+ and CXCR3+CCR6+CD4+ T cells are highly permissive to HIV-1 infection. J Immunol. 2010 DOI: https://doi.org/10.4049/jimmunol.0903058
Jurado, O., Pasquinelli, V., Alvarez, I et al IL17 and IFNγ expression in lymphocytes from patients with active tuberculosis correlates with the severity of the disease. Journal of Leukocyte Biology. 2012; 91: 991-1002. doi:10.1189/jlb.1211619 DOI: https://doi.org/10.1189/jlb.1211619
Feruglio S., Tonby K., Kvale D., et al Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection. Clin Exp Immunol. 2015;179(3): 454–465. DOI: https://doi.org/10.1111/cei.12468
Kim K, Perera R, Tan DB, et al, Circulating mycobacterial-reactive CD4+ T cells with an immunosuppressive phenotype are higher in active tuberculosis than latent tuberculosis infection. Tuberculosis (Edinb). 2014 Sep;94(5):494-501. doi:10.1016/ DOI: https://doi.org/10.1016/j.tube.2014.07.002
Agrawal S, Parkash O, Palaniappan AN, et al. Efficacy of T Regulatory Cells, Th17 Cells and the Associated Markers in Monitoring Tuberculosis Treatment Response. Front Immunol. 2018;9:157. Published 2018 Feb 5. doi:10.3389/fimmu.2018.00157. DOI: https://doi.org/10.3389/fimmu.2018.00157
Nikolova M., Carriere M., Jenabian MA., et al. CD39/Adenosine Pathway Is Involved in AIDS Progression PLoS Pathogens 2011. 7 : e1002110 DOI: https://doi.org/10.1371/journal.ppat.1002110
Chiacchio T, Casetti R, Butera O et al. Characterization of regulatory T cells identified as CD4+CD25highCD39+ in patients with active tuberculosis. Clin Exp Immunol. 2009; 156:463-70 DOI: https://doi.org/10.1111/j.1365-2249.2009.03908.x
Serrano CJ, Castañeda-Delgado JE, Trujillo-Ochoa JL. Regulatory T-cell subsets in response to specific Mycobacterium tuberculosis antigens in vitro distinguish among individuals with different QTF and TST reactivity. Clin Immunol. 2015 ;157(2):145-55. doi: 10.1016/j.clim.2015.02.008... DOI: https://doi.org/10.1016/j.clim.2015.02.008
Kim BS, Lu H, Ichiyama K, et al. Generation of RORγt+antigen-specific T regulatory 17 (Tr17) cells from Foxp3+precursors in autoimmunity Cell Rep. 2017 Oct 3; 21(1):195–207. DOI: https://doi.org/10.1016/j.celrep.2017.09.021
Lee JJ, Kao KC, Chiu YL, et al. Enrichment of Human CCR6+ Regulatory T Cells with Superior Suppressive Activity in Oral Cancer J Immunol. 2017 Jul 15;199(2):467-476. DOI: https://doi.org/10.4049/jimmunol.1601815
Kluger MA, Melderis S, Nosko A, et al. Treg17 cells are programmed by Stat3 to suppress Th17 responses in systemic lupus. Kidney Int. 2016 Jan;89(1):158-66. doi: 10.1038/ki.2015.296. DOI: https://doi.org/10.1038/ki.2015.296
Lin PL, Maiello P, Gideon HPet al. PET CT identifies reactivation risk in cynomolgus macaques with latent M. tuberculosis. PLoS Pathog 2016; 12: e1005739. DOI: https://doi.org/10.1371/journal.ppat.1005739
