Skip to main content

Advertisement

SpringerLink
Log in

The role of T regulatory cell-associated markers in monitoring tuberculosis treatment completion and failure

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Monitoring tuberculosis (TB) treatment success is crucial for clinical decision-making. The only available tool in this regard is sputum microscopy, but it has demerits. Moreover, in case of smear negatives and extrapulmonary TB, an efficient tool is still sought for. Therefore, we evaluated T regulatory cell (Treg)-associated markers (CD25, CD39, and FoxP3) and cellular subsets in monitoring treatment success in treatment-completed groups. Expression profile of various markers and subsets were compared real time among treatment-naive pulmonary TB patients (TN-PTB), followed-up treatment-completed (TC-fu) cohort, and a not followed-up (TC-nfu) cohort. Peripheral blood mononuclear cells from various groups were incubated overnight and were stained with antibodies for specific markers and studied by flow cytometry. In both the treatment-completed groups, a decline in frequencies of CD25+ marker and CD4+CD25+, CD4+CD25+FoxP3, CD4+CD25+CD39+ Treg was observed with clearance of infection, indicating their potential in monitoring treatment success. However, in the case of treatment failure patient (Tfp), a drastic increase in frequency of CD4+CD25+FoxP3+ Treg subset was found, indicating its usefulness in predicting treatment failure. Although the investigation unveils markers useful in predicting treatment success or failure, the findings from this study needs to be validated in a larger cohort.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. World Health Organization, Global Tuberculosis Report 2017. WHO report, Geneva (WHO/HTM/TB/2017.23). 2017. Available from: http://www.who.int/tb/publications/global_report/en/

  2. Parkash O, Agrawal S, Madhan MK. T regulatory cells: Achilles’ heel of Mycobacterium tuberculosis infection? Immunol Res. 2015;62:386–98. https://doi.org/10.1007/s12026-015-8654-0.

    Article  CAS  PubMed  Google Scholar 

  3. How SH, Kuan YC, Ng TH, Razali MR, Fauzi AR. Monitoring treatment response in sputum smear positive pulmonary tuberculosis patients: comparison of weight gain, sputum conversion and chest radiograph. Malays J Pathol. 2014;36:91–6.

    CAS  PubMed  Google Scholar 

  4. Horne DJ, Royce SE, Gooze L, Narita M, Hopewell PC, Nahid P, et al. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect Dis. 2010;10:387–94. https://doi.org/10.1016/S1473-3099(10)70071-2.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Caulfield AJ, Wengenack NJ. Diagnosis of active tuberculosis disease: from microscopy to molecular techniques. J Clin Tuberc Other Mycobact Dis. 2016;4:33–43. https://doi.org/10.1016/j.jctube.2016.05.005.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Agrawal S, Parkash O, Palaniappan AN, Bhatia AK, Kumar S, Chauhan DS, et al. Efficacy of T regulatory cells, Th17 cells and the associated markers in monitoring tuberculosis treatment response. Front Immunol. 2018;9:157. https://doi.org/10.3389/fimmu.2018.00157.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Adekambi T, Ibegbu CC, Cagle S, Kalokhe AS, Wang YF, Hu Y, et al. Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response. J Clin Invest. 2015;125(9):3723. https://doi.org/10.1172/JCI83279.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Treatment of Tuberculosis: guidelines. 4th ed. Geneva: World Health Organisation 2010.

  9. Allen BW. Modified Petroff technique treatment of specimens, chapter 3. In: Baker FJ, editor. Mycobacteria isolation, identification and sensitivity testing. London: Butter Worth and Co; 1968. p. 9–16.

    Google Scholar 

  10. Guyot-Revol V, Innes JA, Hackforth S, Hinks T, Lalvani A. Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. Am J Respir Crit Care Med. 2006;173:803–10. https://doi.org/10.1164/rccm.200508-1294OC.

    Article  CAS  PubMed  Google Scholar 

  11. Welsh KJ, Risin SA, Actor JK, Hunter RL. Immunopathology of postprimary tuberculosis: increased T-regulatory cells and DEC-205-positive foamy macrophages in cavitary lesions. Clin Dev Immunol. 2011;2011:307631–9. https://doi.org/10.1155/2011/307631.

    Article  PubMed  Google Scholar 

  12. Wu YE, Peng WG, Cai YM, Zheng GZ, Zheng GL, Lin JH, et al. Decrease in CD4+CD25+FoxP3+ Treg cells after resection in the treatment of cavity multidrug-resistant tuberculosis. Int J Infect Dis. 2010;14:e815–22. https://doi.org/10.1016/j.ijid.2010.04.005.

    Article  CAS  PubMed  Google Scholar 

  13. Churina EG, Urazova OI, Novitskiy VV. The role of Foxp3-expressing regulatory T cells and T helpers in immunopathogenesis of multidrug resistant pulmonary tuberculosis. Tuberc Res Treat. 2012;2012:931291–9. https://doi.org/10.1155/2012/931291.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lim HJ, Park JS, Cho YJ, Yoon HI, Park KU, Lee CT, et al. CD4(+)FoxP3(+) T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis. Tuberculosis (Edinb). 2013;93:523–8. https://doi.org/10.1016/j.tube.2013.06.001.

    Article  CAS  Google Scholar 

  15. Li N, Xie WP, Kong H, Min R, Hu CM, Zhou XB, et al. Enrichment of regulatory T-cells in blood of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2015;19:1230–8. https://doi.org/10.5588/ijtld.15.0148.

    Article  CAS  PubMed  Google Scholar 

  16. Feruglio SL, Tonby K, Kvale D, Dyrhol-Riise AM. Early dynamics of T helper cell cytokines and T regulatory cells in response to treatment of active Mycobacterium tuberculosis infection. Clin Exp Immunol. 2014;179:454–65. https://doi.org/10.1111/cei.12468.

    Article  CAS  Google Scholar 

  17. de Almeida AS, Fiske CT, Sterling TR, Kalams SA. Increased frequency of regulatory T cells and T lymphocyte activation in persons with previously treated extrapulmonary tuberculosis. Clin Vaccine Immunol. 2012;19:45–52. https://doi.org/10.1128/CVI.05263-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ribeiro-Rodrigues R, Resende Co T, Rojas R, Toossi Z, Dietze R, Boom WH, et al. A role for CD4+CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol. 2006;144:25–34. https://doi.org/10.1111/j.1365-2249.2006.03027.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Singh A, Dey AB, Mohan A, Sharma PK, Mitra DK. Foxp3+ regulatory T cells among tuberculosis patients: impact on prognosis and restoration of antigen specific IFN-γ producing T cells. PLoS One. 2012;7:e44728. https://doi.org/10.1371/journal.pone.0044728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jackson-Sillah D, Cliff JM, Mensah GI, Dickson E, Sowah S, Tetteh JK, et al. Recombinant ESAT-6-CFP10 fusion protein induction of Th1/Th2 cytokines and FoxP3 expressing Treg cells in pulmonary TB. PLoS One. 2013;8:e68121. https://doi.org/10.1371/journal.pone.0068121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Arram EO, Hassan R, Saleh M. Increased frequency of CD4+CD25+FoxP3+ circulating regulatory T cells (Treg) in tuberculous patients. Egypt J Chest Dis Tuberc. 2014;63:167–72. https://doi.org/10.1016/j.ejcdt.2013.10.013.

    Article  Google Scholar 

  22. Chen X, Zhou B, Li M, Deng Q, Wu X, Le X, et al. CD4(+) CD25(+) FoxP3(+) regulatory T cells suppress Mycobacterium tuberculosis immunity in patients with active disease. Clin Immunol. 2007;123:50–9. https://doi.org/10.1016/j.clim.2006.11.009.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Ms. Sonali Agrawal, a DST (Department of Science and Technology, Govt. of India) INSPIRE fellow, would like to acknowledge DST for providing research fellowship for pursuing research. The authors also thank Dr. Luke Elizabeth Hannah, Scientist, Department of HIV, National Institute for Research in Tuberculosis (NIRT), Chennai, for her support and help in performing Quantiferon TB Gold testing and Dr. Ponnuraja, Scientist, Department of Statistics, NIRT, Chennai, for his guidance in statistical analysis. The technical help provided by Mr. Vijay Dua (X-ray technician) and Mr. Ajay Kumar Jain (Hematology department) is kindly acknowledged. The authors are grateful to Mr. Ravi Kumar and Mr. Pushpendra Singh for their help in patient recruitment.

Funding

This study was funded by the Defence Research and Development Organization, India (DRDE-P1-2015/Task-216).

Author information

Authors and Affiliations

  1. Department of Immunology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, India

    Sonali Agrawal, Om Parkash & M. Madhan Kumar

  2. Department of Biotechnology, GLA University, Mathura, India

    Sonali Agrawal & Ashok K. Bhatia

  3. Department of Clinic, National Institute for Research in Tuberculosis, Chennai, India

    Alangudi Natarajan Palaniappan

  4. Department of Tuberculosis & Chest Diseases, Sarojini Naidu Medical College, Agra, India

    Santosh Kumar

  5. Department of Microbiology and Molecular Biology, National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, India

    Devendra S. Chauhan

Authors
  1. Sonali Agrawal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Om Parkash
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alangudi Natarajan Palaniappan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ashok K. Bhatia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Santosh Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Devendra S. Chauhan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. Madhan Kumar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Madhan Kumar.

Ethics declarations

Ethical approval was obtained from Institutional Human Ethics Committee (IHEC) before initiating the study, and written informed consent from all the study subjects were received before collecting the samples. All the study participants were recruited from National JALMA institute for leprosy and other mycobacterial diseases (NJIL&OMD), Agra

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Agrawal, S., Parkash, O., Palaniappan, A.N. et al. The role of T regulatory cell-associated markers in monitoring tuberculosis treatment completion and failure. Immunol Res 66, 620–631 (2018). https://doi.org/10.1007/s12026-018-9022-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-018-9022-7

Keywords

Search

Navigation