Skip to main content

Advertisement

Log in

Modulatory effect of Tim-3/Galectin-9 axis on T-cell-mediated immunity in pulmonary tuberculosis

  • Published:
Journal of Biosciences Aims and scope Submit manuscript

Abstract

Patients affected by pulmonary tuberculosis (PTB) manifest deficiencies in innate cellular immunity. The Tim-3/Galectin-9 axis is an important regulator of Th1 cell immunity, leading to Th1 cell apoptosis. Herein, this study aims to clarify the underlying roles of the Tim-3/Galectin-9 axis in T-cell immunity in PTB. Peripheral blood mononuclear cells (PBMCs) were extracted from subjects with and without PTB to examine the expression of CD4, CD8, CD25, and Tim-3 under the stimulation of Mycobacterium tuberculosis (MTB) and purified protein derivative (PPD). In addition, the expression of Tim-3 and Galectin-9 in PBMCs was determined. The Tim-3/Galectin-9 axis in the PBMCs was activated or blocked to detect the secreted levels of IFN-γ, TNF-α, IL-2, and IL-22. MTB stimulation increased the expression of CD4, CD8, CD25, Tim-3, and Galectin-9 in PBMCs. The blockade of Tim-3/Galectin-9 axis resulted in reduced secretion of IFN-γ, TNF-α, IL-2, and IL-22 from T-cells. Moreover, Tim-3+CD4+T, Tim-3+CD8+, and Tim-3+CD25+T cells exhibited a greater ability to inhibit the replication of MTB in macrophages. Taken conjointly, the blockade of Tim-3/Galectin-9 axis inhibits the secretion of inflammatory cytokines in T-cells to regulate the T-cell immunity in PTB.

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

Access this article

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

Instant access to the full article PDF.

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  • Abhimanyu BM, Jha P and Indian Genome Variation C 2012 Footprints of genetic susceptibility to pulmonary tuberculosis: cytokine gene variants in north Indians. Indian J. Med. Res. 135 763–770

    CAS  PubMed Central  Google Scholar 

  • Abreu R, Essler L, Loy A, Quinn F and Giri P 2018 Heparin inhibits intracellular Mycobacterium tuberculosis bacterial replication by reducing iron levels in human macrophages. Sci. Rep. 8 7296

    Article  Google Scholar 

  • Chai D, Zhang L, Xi S, Cheng Y, Jiang H and Hu R 2018 Nrf2 Activation induced by Sirt1 ameliorates acute lung injury after intestinal ischemia/reperfusion through NOX4-mediated gene regulation. Cell Physiol. Biochem. 46 781–792

    Article  CAS  Google Scholar 

  • Chen X, Zhou B, Li M, Deng Q, Wu X, Le X, Wu C, Larmonier N, Zhang W, Zhang H, Wang H and Katsanis E 2007 CD4(+)CD25(+)FoxP3(+) regulatory T cells suppress Mycobacterium tuberculosis immunity in patients with active disease. Clin. Immunol. 123 50–59

    Article  CAS  Google Scholar 

  • Dardalhon V, Anderson AC, Karman J, Apetoh L, Chandwaskar R, Lee DH, Cornejo M, Nishi N, Yamauchi A, Quintana FJ, Sobel RA, Hirashima M and Kuchroo VK 2010 Tim-3/galectin-9 pathway: regulation of Th1 immunity through promotion of CD11b+Ly-6G+ myeloid cells. J. Immunol. 185 1383–1392

    Article  CAS  Google Scholar 

  • Eurosurveillance Editorial Team 2018 Note from the editors: World Tuberculosis Day 2018 and Special issue-Screening and prevention of infectious diseases in newly arrived migrants in Europe. Euro Surveill 23 180322-1 https://doi.org/10.2807/1560-7917.ES.2018.23.12.180322-1

    Article  PubMed Central  Google Scholar 

  • Green AM, Difazio R and 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

    Article  CAS  Google Scholar 

  • Gupta S, Shenoy VP, Mukhopadhyay C, Bairy I and Muralidharan S 2011 Role of risk factors and socio-economic status in pulmonary tuberculosis: a search for the root cause in patients in a tertiary care hospital, South India. Trop. Med. Int. Health 16 74–78

    Article  Google Scholar 

  • Guthrie JL, Delli Pizzi A, Roth D, Kong C, Jorgensen D, Rodrigues M, Tang P, Cook VJ, Johnston J and Gardy JL 2018 Genotyping and Whole-Genome Sequencing to Identify Tuberculosis Transmission to Pediatric Patients in British Columbia, Canada, 2005–2014. J. Infect. Dis. 218 1155–1163

    Article  Google Scholar 

  • Huang Y, Wu Q, Xu S, Zhong J, Chen S, Xu J, Zhu L, He H and Wang X 2017 Laboratory-based surveillance of extensively drug-resistant tuberculosis in eastern China. Microb. Drug Resist. 23 236–240

    Article  CAS  Google Scholar 

  • Isabel BE and Rogelio HP 2014 Pathogenesis and immune response in tuberculous meningitis. Malays. J. Med. Sci. 21 4–10

    PubMed  PubMed Central  Google Scholar 

  • Jayaraman P, Sada-Ovalle I, Beladi S, Anderson AC, Dardalhon V, Hotta C, Kuchroo VK and Behar SM 2010 Tim3 binding to galectin-9 stimulates antimicrobial immunity. J. Exp. Med. 207 2343–2354

    Article  CAS  Google Scholar 

  • Kuchroo VK, Meyers JH, Umetsu DT and DeKruyff RH 2006 TIM family of genes in immunity and tolerance. Adv. Immunol. 91 227–249

    Article  CAS  Google Scholar 

  • Lai SW, Wang IK, Lin CL, Chen HJ and Liao KF 2014 Splenectomy correlates with increased risk of pulmonary tuberculosis: a case-control study in Taiwan. Clin. Microbiol. Infect. 20 764–767

    Article  Google Scholar 

  • Li H, Wu K, Tao K, Chen L, Zheng Q, Lu X, Liu J, Shi L, Liu C, Wang G and Zou W 2012 Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56 1342–1351

    Article  CAS  Google Scholar 

  • Man DK, Chow MY, Casettari L, Gonzalez-Juarrero M and Lam JK 2016 Potential and development of inhaled RNAi therapeutics for the treatment of pulmonary tuberculosis. Adv. Drug Deliv. Rev. 102 21–32

    Article  CAS  Google Scholar 

  • Mariat C, Sanchez-Fueyo A, Alexopoulos SP, Kenny J, Strom TB and Zheng XX 2005 Regulation of T cell dependent immune responses by TIM family members. Philos. Trans. R. Soc. Lond. B Biol. Sci. 360 1681–1685

    Article  CAS  Google Scholar 

  • Monney L, Sabatos CA, Gaglia JL, Ryu A, Waldner H, Chernova T, Manning S, Greenfield EA, Coyle AJ, Sobel RA, Freeman GJ and Kuchroo VK 2002 Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease. Nature 415 536–541

    Article  CAS  Google Scholar 

  • Nebbia G, Peppa D, Schurich A, Khanna P, Singh HD, Cheng Y, Rosenberg W, Dusheiko G, Gilson R, ChinAleong J, Kennedy P and Maini MK 2012 Upregulation of the Tim-3/galectin-9 pathway of T cell exhaustion in chronic hepatitis B virus infection. PLoS ONE 7 e47648

    Article  CAS  Google Scholar 

  • Nemeth J, Winkler HM, Boeck L, Adegnika AA, Clement E, Mve TM, Kremsner PG and Winkler S 2011 Specific cytokine patterns of pulmonary tuberculosis in Central Africa. Clin. Immunol. 138 50–59

    Article  CAS  Google Scholar 

  • Ortiz-Martinez Y 2017 Assessing worldwide research productivity on tuberculosis over a 40-year period: A bibliometric analysis. Indian J. Tuberc. 64 235–236

    Article  Google Scholar 

  • Park JS, Kang YA, Kwon SY, Yoon HI, Chung JH, Lee CT and Lee JH 2010 Nested PCR in lung tissue for diagnosis of pulmonary tuberculosis. Eur. Respir. J. 35 851–857

    Article  CAS  Google Scholar 

  • Qiu Y, Chen J, Liao H, Zhang Y, Wang H, Li S, Luo Y, Fang D, Li G, Zhou B, Shen L, Chen CY, Huang D, Cai J, Cao K, Jiang L, Zeng G and Chen ZW 2012 Tim-3-expressing CD4+ and CD8+ T cells in human tuberculosis (TB) exhibit polarized effector memory phenotypes and stronger anti-TB effector functions. PLoS Pathog. 8 e1002984

    Article  CAS  Google Scholar 

  • Reddy PB, Sehrawat S, Suryawanshi A, Rajasagi NK, Mulik S, Hirashima M and Rouse BT 2011 Influence of galectin-9/Tim-3 interaction on herpes simplex virus-1 latency. J. Immunol. 187 5745–5755

    Article  CAS  Google Scholar 

  • Sada-Ovalle I, Ocana-Guzman R, Perez-Patrigeon S, Chavez-Galan L, Sierra-Madero J, Torre-Bouscoulet L and Addo MM 2015 Tim-3 blocking rescue macrophage and T cell function against Mycobacterium tuberculosis infection in HIV+ patients. J. Int. AIDS Soc. 18 20078

    Article  Google Scholar 

  • Sakuishi K, Jayaraman P, Behar SM, Anderson AC and Kuchroo VK 2011 Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 32 345–349

    Article  CAS  Google Scholar 

  • Shafiani S, Tucker-Heard G, Kariyone A, Takatsu K and Urdahl KB 2010 Pathogen-specific regulatory T cells delay the arrival of effector T cells in the lung during early tuberculosis. J. Exp. Med. 207 1409–1420

    Article  CAS  Google Scholar 

  • Srivastav NC, Rai D, Tse C, Agrawal B, Kunimoto DY and Kumar R 2010 Inhibition of mycobacterial replication by pyrimidines possessing various C-5 functionalities and related 2’-deoxynucleoside analogues using in vitro and in vivo models. J. Med. Chem. 53 6180–6187

    Article  CAS  Google Scholar 

  • Subbian S, Tsenova L, O’Brien P, Yang G, Koo MS, Peixoto B, Fallows D, Zeldis JB, Muller G and Kaplan G 2011 Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology. Am. J. Pathol. 179 289–301

    Article  CAS  Google Scholar 

  • Urdahl KB, Shafiani S and Ernst JD 2011 Initiation and regulation of T-cell responses in tuberculosis. Mucosal Immunol. 4 288–293

    Article  CAS  Google Scholar 

  • Wang F, He W, Yuan J, Wu K, Zhou H, Zhang W and Chen ZK 2008 Activation of Tim-3-Galectin-9 pathway improves survival of fully allogeneic skin grafts. Transpl. Immunol. 19 12–19

    Article  Google Scholar 

  • Wang F, Hou H, Wu S, Tang Q, Huang M, Yin B, Huang J, Liu W, Mao L, Lu Y and Sun Z 2015 Tim-3 pathway affects NK cell impairment in patients with active tuberculosis. Cytokine 76 270–279

    Article  CAS  Google Scholar 

  • Wu CY, Hu HY, Pu CY, Huang N, Shen HC, Li CP and Chou YJ 2011 Pulmonary tuberculosis increases the risk of lung cancer: a population-based cohort study. Cancer 117 618–624

    Article  Google Scholar 

  • Zhang Y, Ma CJ, Wang JM, Ji XJ, Wu XY, Moorman JP and Yao ZQ 2012 Tim-3 regulates pro- and anti-inflammatory cytokine expression in human CD14+ monocytes. J. Leukoc. Biol. 91 189–196

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by National Natural Science Foundation of China (No. 81670080). We appreciate the helpful comments from the reviewers of this paper.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Jing-Hua Wang.

Additional information

Communicated by Dipankar Nandi.

Corresponding editor: Dipankar Nandi

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Figure 1

Flow cytometric data for sorting CD8+ T cells from healthy controls, LPTB patients and PTB patients. In the HC group, n = 20; in the LPTB group, n = 40; and in the active PTB group, n = 50 (EPS 10283 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kang, J., Wei, ZF., Li, MX. et al. Modulatory effect of Tim-3/Galectin-9 axis on T-cell-mediated immunity in pulmonary tuberculosis. J Biosci 45, 60 (2020). https://doi.org/10.1007/s12038-020-0023-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12038-020-0023-z

Keywords

Navigation