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.
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
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
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
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
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
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
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
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
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
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
Isabel BE and Rogelio HP 2014 Pathogenesis and immune response in tuberculous meningitis. Malays. J. Med. Sci. 21 4–10
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
Kuchroo VK, Meyers JH, Umetsu DT and DeKruyff RH 2006 TIM family of genes in immunity and tolerance. Adv. Immunol. 91 227–249
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
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
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
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
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
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
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
Ortiz-Martinez Y 2017 Assessing worldwide research productivity on tuberculosis over a 40-year period: A bibliometric analysis. Indian J. Tuberc. 64 235–236
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
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
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
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
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
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
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
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
Urdahl KB, Shafiani S and Ernst JD 2011 Initiation and regulation of T-cell responses in tuberculosis. Mucosal Immunol. 4 288–293
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
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
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
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
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
Corresponding author
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
About this article
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
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12038-020-0023-z