CD4+ regulatory T cells and CD4+ activated T cells in new active and relapse tuberculosis

Pacifique Ndishimye; Fathiah Zakham; Clarisse Musanabaganwa; Patrick Migambi; Cenariu Mihai; Olga Soritau; Mohammed El Mzibri; Carmen Monica Pop; Leon Mutesa

doi:10.14715/cmb/2019.65.8.4

Issue

Vol. 65 No. 8: Issue 8

Issue Published : January 15, 2020

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CD4+ regulatory T cells and CD4+ activated T cells in new active and relapse tuberculosis

https://doi.org/10.14715/cmb/2019.65.8.4

Pacifique Ndishimye

Medical Research Centre, Rwanda Biomedical Centre, Kigali, Rwanda

http://orcid.org/0000-0003-3285-2622

Fathiah Zakham

Department of Laboratory Medicine, Faculty of Medicine and Health Sciences, Hodeidah University, Yemen

http://orcid.org/0000-0003-2505-7217

Clarisse Musanabaganwa

Medical Research Centre, Rwanda Biomedical Centre, Kigali, Rwanda

Patrick Migambi

Tuberculosis and Other Respiratory Diseases Division, Rwanda Biomedical Center, Kigali, Rwanda

Cenariu Mihai

Immunopathology Laboratory, UASVM, Cluj Napoca, Romania

Olga Soritau

"Iuliu HaÈ›ieganu" University of Medicine and Pharmacy, Cluj Napoca, Romania

Mohammed El Mzibri

Life Science Division - CNESTEN, Rabat, Morocco

http://orcid.org/0000-0002-3148-1527

Carmen Monica Pop

"Iuliu HaÈ›ieganu" University of Medicine and Pharmacy, Cluj Napoca, Romania

Leon Mutesa

Center for Human Genetics, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda

Corresponding Author(s) : Mohammed El Mzibri

mzibri@yahoo.com

Cellular and Molecular Biology, Vol. 65 No. 8: Issue 8
Article Published : December 31, 2019

Abstract

The aim of the present study was to examine characteristics of tuberculosis (TB) patients with different clinical forms and to study the frequency of Regulatory T cells (Treg cells) and Activated T cells in patients with new active and relapse TB. Forty-five pulmonary TB patients and a control group of 15 healthy individuals were enrolled in this study. Of the 45 TB patients, 15 were new cases with drug-susceptible active TB and 30 were relapsed cases (15 drug-susceptible and 15 multidrug resistant-TB). The age of study participants ranged from 21 to 68 years old. According to sex presentation, males were appreciably highly affected than females with a sex ratio of 2. The patients reported a mean recent weight loss of 8.9 kg. The Erythrocyte Sedimentation Rate was high in TB group, far exceeding the normal value. The results revealed that the number of CD3+ CD4+ T-cells significantly decreased whereas the level of blood Treg cells and expression of activation markers CD38 and HLA-DR on CD4+ T-cells significantly increased in TB group compared with the control group (p<0.05). The frequency of Treg cells was significantly higher in the TB group than the control group. Both the patients with new active TB and relapse TB demonstrated significantly higher levels of CD4+FoxP3+ Treg compared to healthy subjects (p<0.05). A high and significant percentage of Treg cells were found in patients with DS active TB than patients with MDR relapse TB. Interestingly, the frequency of CD4+FoxP3+ cells also differs according to the sputum smear microscopy status. The presence of high numbers of Treg cells and corresponding high immune activation may be an unfavourable factor that can predispose individuals to different clinical forms of TB, including relapse TB.

Keywords

Tuberculosis Regulatory T-cells CD4 T cell activation FoxP3 protein Relapse Disease susceptibility Multidrug-resistant tuberculosis.

Ndishimye, P., Zakham, F., Musanabaganwa, C., Migambi, P., Mihai, C., Soritau, O., El Mzibri, M., Pop, C. M., & Mutesa, L. (2019). CD4+ regulatory T cells and CD4+ activated T cells in new active and relapse tuberculosis. Cellular and Molecular Biology, 65(8), 18–22. https://doi.org/10.14715/cmb/2019.65.8.4

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References

WHO. WHO Global tuberculosis report 2017. World Health Organization Press. 2017.
Dolma KG, Adhikari L, Dadul P, Laden T, Singhi L, Mahanta J. A study on the assessment of retreatment tuberculosis patients attending the DOTS centre in Sikkim, India from 2002-2010. Res J Infect Dis. 2013; 1: 3-7.
van Crevel R, Ottenhoff THM, van der Meer JWM. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev. 2002; 15: 294-309.
Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: How do they suppress immune responses? International Immunology. 2009; 21: 1105-1111.
Gondek DC, Lu L-F, Quezada SA, Sakaguchi S, Noelle RJ. Cutting Edge: Contact-Mediated Suppression by CD4+CD25+ Regulatory Cells Involves a Granzyme B-Dependent, Perforin-Independent Mechanism. J Immunol. 2005; 174: 1783-1786.
Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ. Granzyme B and Perforin Are Important for Regulatory T Cell-Mediated Suppression of Tumor Clearance. Immunity. 2007; 27: 635-646.
Hua S, Lécuroux C, Sáez-Cirión A, Pancino G, Girault I, Versmisse P, Boufassa F, Taulera O, Sinet M, Lambotte O, Venet A. Potential role for HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppression and cytotoxicity in HIV controllers. PLoS One. 2014; 9: e101920.
Kursar M, Koch M, Mittrücker H-W, Nouailles G, Bonhagen K, Kamradt T, Kaufmann SH. Cutting Edge: Regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J Immunol. 2007; 178: 2661-2665.
Chen X, Zhou B, Li M, Deng Q, Wu X, Le X, Wu C, Larmonier N, Zhang W, Zhang H, Wang H, Katsanis E. CD4+CD25+FoxP3+regulatory T cells suppress Mycobacterium tuberculosis immunity in patients with active disease. Clin Immunol. 2007; 123: 50-59.
Hougardy JM, Verscheure V, Locht C, Mascart F. In vitro expansion of CD4+CD25highFOXP3+CD127low/- regulatory T cells from peripheral blood lymphocytes of healthy Mycobacterium tuberculosis-infected humans. Microbes Infect. 2007; 9: 1325-1332.
He XY, Xiao L, Chen HB, Hao J, Li J, Wang YJ, He K, Gao Y, Shi BY. T regulatory cells and Th1/Th2 cytokines in peripheral blood from tuberculosis patients. Eur J Clin Microbiol Infect Dis. 2010; 29: 643-650.
Barcelos W, Martins-Filho OA, Guimarí£es TMPD, Oliveira MHP, Spíndola-de-Miranda S, Carvalho BN, Toledo Vde P. Peripheral blood mononuclear cells immunophenotyping in pulmonary tuberculosis patients before and after treatment. Microbiol Immunol. 2006; 50: 597-605.
Li N, Xie WP, Kong H, Min R, Hu CM, Zhou XB, Lu ZM, Ji XH, Wang H. Enrichment of regulatory T-cells in blood of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2015; 19: 1230-1238.
Kubica G, Kent K. Public health mycobacteriology: a guide for the level III laboratory. Centers for Disease Control, U.S. Department of Health and Human Services, Atlanta, GA. 1985.
Agarwala A, Roy P, Saha K, Shamim S. The profile and treatment outcomes of sputum smear positive pulmonary tuberculosis re-treatment cases, in a district medical college of West Bengal, India. J Assoc Chest Physicians. 2014; 2 : 63-67.
Furuhashi K, Shirai T, Suda T, Chida K. Inflammatory markers in active pulmonary tuberculosis: association with Th1/Th2 and Tc1/Tc2 balance. Kekkaku. 2012; 87: 1-7.
Oliva VM, CezÙ„rio GAG, Cocato RA, Marcondes-Machado J. Pulmonary tuberculosis: hematology, serum biochemistry and the relation with the disease duration. J Venom Anim Toxins Incl Trop Dis. 2008; 14: 71-81.
Jones BE, Oo MM, Taikwel EK, Qian D, Kumar a, Maslow ER, Barnes PF. CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis. Clin Infect Dis. 1997; 24: 988-991.
Rodrigues DSS, Medeiros EAS, Weckx LY, Bonnez W, Salomí£o R, Kallas EG. Immunophenotypic characterization of peripheral T lymphocytes in Mycobacterium tuberculosis infection and disease. Clin Exp Immunol. 2002; 128: 149-154.
Wu YE, Zhang SW, Peng WG, Li KS, Li K, Jiang JK, Lin JH, Cai YM. Changes in lymphocyte subsets in the peripheral blood of patients with active pulmonary tuberculosis. J Int Med Res. 2009; 37: 1742-1749.
Hertoghe T, Wajja A, Ntambi L, Okwera A, Aziz MA, Hirsch C, Johnson J, Toossi Z, Mugerwa R, Mugyenyi P, Colebunders R, Ellner J, Vanham G. T cell activation, apoptosis and cytokine dysregulation in the (co)pathogenesis of HIV and pulmonary tuberculosis (TB). Clin Exp Immunol. 2000; 122: 350-357.
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: 803-810.
Hougardy JM, Place S, Hildebrand M, Drowart A, Debrie AS, Locht C, Mascart F. Regulatory T cells depress immune responses to protective antigens in active tuberculosis. Am J Respir Crit Care Med. 2007; 176: 409-416.
Marin ND, París SC, Vélez VM, Rojas C a, Rojas M, García LF. Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. Tuberculosis (Edinb). 2010; 90: 252-61.
Ribeiro-Rodrigues R, Resende Co T, Rojas R, Toossi Z, Dietze R, Boom WH, Maciel E, Hirsch CS. A role for CD4+ CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol. 2006; 144: 25-34.
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.
Lim HJ, Park JS, Cho YJ, Yoon H Il, Park KU, Lee CT, Lee JH. CD4+FoxP3+T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis. Tuberculosis. 2013; 93: 523-528.
Mbow M, Santos NSS, Camara M, Ba A, Niang A, Daneau G, Wade D, Diallo AA, Toupane M, Diakhaté M, Lèye N, Diaw PA, Mboup S, Kestens L, Dieye TN. HIV and Tuberculosis co-infection impacts T-cell activation markers but not the numbers subset of regulatory T-cells in HIV-1 infected patients. Afr J Lab Med. 2013; 2 : a76.
Churina EG, Urazova OI, Novitskiy V V. The Role of Foxp3-Expressing Regulatory T Cells and T Helpers in Immunopathogenesis of Multidrug Resistant Pulmonary Tuberculosis. Tuberc Res Treat. 2012; 2012: 931291.
Green AM, Mattila JT, Bigbee CL, Bongers KS, Lin PL, Flynn JL. CD4(+) regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection. J Infect Dis. 2010; 202: 533-41.
Suchard MS, Mayne E, Green VA, Shalekoff S, Donninger SL, Stevens WS, Gray CM, Tiemessen CT. FOXP3 expression is upregulated in CD4+T cells in progressive HIV-1 infection and is a marker of disease severity. PLoS One. 2010; 5: e11762.

References

WHO. WHO Global tuberculosis report 2017. World Health Organization Press. 2017.

Dolma KG, Adhikari L, Dadul P, Laden T, Singhi L, Mahanta J. A study on the assessment of retreatment tuberculosis patients attending the DOTS centre in Sikkim, India from 2002-2010. Res J Infect Dis. 2013; 1: 3-7.

van Crevel R, Ottenhoff THM, van der Meer JWM. Innate immunity to Mycobacterium tuberculosis. Clin Microbiol Rev. 2002; 15: 294-309.

Sakaguchi S, Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T. Regulatory T cells: How do they suppress immune responses? International Immunology. 2009; 21: 1105-1111.

Gondek DC, Lu L-F, Quezada SA, Sakaguchi S, Noelle RJ. Cutting Edge: Contact-Mediated Suppression by CD4+CD25+ Regulatory Cells Involves a Granzyme B-Dependent, Perforin-Independent Mechanism. J Immunol. 2005; 174: 1783-1786.

Cao X, Cai SF, Fehniger TA, Song J, Collins LI, Piwnica-Worms DR, Ley TJ. Granzyme B and Perforin Are Important for Regulatory T Cell-Mediated Suppression of Tumor Clearance. Immunity. 2007; 27: 635-646.

Hua S, Lécuroux C, Sáez-Cirión A, Pancino G, Girault I, Versmisse P, Boufassa F, Taulera O, Sinet M, Lambotte O, Venet A. Potential role for HIV-specific CD38-/HLA-DR+ CD8+ T cells in viral suppression and cytotoxicity in HIV controllers. PLoS One. 2014; 9: e101920.

Kursar M, Koch M, Mittrücker H-W, Nouailles G, Bonhagen K, Kamradt T, Kaufmann SH. Cutting Edge: Regulatory T cells prevent efficient clearance of Mycobacterium tuberculosis. J Immunol. 2007; 178: 2661-2665.

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

Hougardy JM, Verscheure V, Locht C, Mascart F. In vitro expansion of CD4+CD25highFOXP3+CD127low/- regulatory T cells from peripheral blood lymphocytes of healthy Mycobacterium tuberculosis-infected humans. Microbes Infect. 2007; 9: 1325-1332.

He XY, Xiao L, Chen HB, Hao J, Li J, Wang YJ, He K, Gao Y, Shi BY. T regulatory cells and Th1/Th2 cytokines in peripheral blood from tuberculosis patients. Eur J Clin Microbiol Infect Dis. 2010; 29: 643-650.

Barcelos W, Martins-Filho OA, Guimarí£es TMPD, Oliveira MHP, Spíndola-de-Miranda S, Carvalho BN, Toledo Vde P. Peripheral blood mononuclear cells immunophenotyping in pulmonary tuberculosis patients before and after treatment. Microbiol Immunol. 2006; 50: 597-605.

Li N, Xie WP, Kong H, Min R, Hu CM, Zhou XB, Lu ZM, Ji XH, Wang H. Enrichment of regulatory T-cells in blood of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2015; 19: 1230-1238.

Kubica G, Kent K. Public health mycobacteriology: a guide for the level III laboratory. Centers for Disease Control, U.S. Department of Health and Human Services, Atlanta, GA. 1985.

Agarwala A, Roy P, Saha K, Shamim S. The profile and treatment outcomes of sputum smear positive pulmonary tuberculosis re-treatment cases, in a district medical college of West Bengal, India. J Assoc Chest Physicians. 2014; 2 : 63-67.

Furuhashi K, Shirai T, Suda T, Chida K. Inflammatory markers in active pulmonary tuberculosis: association with Th1/Th2 and Tc1/Tc2 balance. Kekkaku. 2012; 87: 1-7.

Oliva VM, CezÙ„rio GAG, Cocato RA, Marcondes-Machado J. Pulmonary tuberculosis: hematology, serum biochemistry and the relation with the disease duration. J Venom Anim Toxins Incl Trop Dis. 2008; 14: 71-81.

Jones BE, Oo MM, Taikwel EK, Qian D, Kumar a, Maslow ER, Barnes PF. CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis. Clin Infect Dis. 1997; 24: 988-991.

Rodrigues DSS, Medeiros EAS, Weckx LY, Bonnez W, Salomí£o R, Kallas EG. Immunophenotypic characterization of peripheral T lymphocytes in Mycobacterium tuberculosis infection and disease. Clin Exp Immunol. 2002; 128: 149-154.

Wu YE, Zhang SW, Peng WG, Li KS, Li K, Jiang JK, Lin JH, Cai YM. Changes in lymphocyte subsets in the peripheral blood of patients with active pulmonary tuberculosis. J Int Med Res. 2009; 37: 1742-1749.

Hertoghe T, Wajja A, Ntambi L, Okwera A, Aziz MA, Hirsch C, Johnson J, Toossi Z, Mugerwa R, Mugyenyi P, Colebunders R, Ellner J, Vanham G. T cell activation, apoptosis and cytokine dysregulation in the (co)pathogenesis of HIV and pulmonary tuberculosis (TB). Clin Exp Immunol. 2000; 122: 350-357.

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: 803-810.

Hougardy JM, Place S, Hildebrand M, Drowart A, Debrie AS, Locht C, Mascart F. Regulatory T cells depress immune responses to protective antigens in active tuberculosis. Am J Respir Crit Care Med. 2007; 176: 409-416.

Marin ND, París SC, Vélez VM, Rojas C a, Rojas M, García LF. Regulatory T cell frequency and modulation of IFN-gamma and IL-17 in active and latent tuberculosis. Tuberculosis (Edinb). 2010; 90: 252-61.

Ribeiro-Rodrigues R, Resende Co T, Rojas R, Toossi Z, Dietze R, Boom WH, Maciel E, Hirsch CS. A role for CD4+ CD25+ T cells in regulation of the immune response during human tuberculosis. Clin Exp Immunol. 2006; 144: 25-34.

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.

Lim HJ, Park JS, Cho YJ, Yoon H Il, Park KU, Lee CT, Lee JH. CD4+FoxP3+T regulatory cells in drug-susceptible and multidrug-resistant tuberculosis. Tuberculosis. 2013; 93: 523-528.

Mbow M, Santos NSS, Camara M, Ba A, Niang A, Daneau G, Wade D, Diallo AA, Toupane M, Diakhaté M, Lèye N, Diaw PA, Mboup S, Kestens L, Dieye TN. HIV and Tuberculosis co-infection impacts T-cell activation markers but not the numbers subset of regulatory T-cells in HIV-1 infected patients. Afr J Lab Med. 2013; 2 : a76.

Churina EG, Urazova OI, Novitskiy V V. The Role of Foxp3-Expressing Regulatory T Cells and T Helpers in Immunopathogenesis of Multidrug Resistant Pulmonary Tuberculosis. Tuberc Res Treat. 2012; 2012: 931291.

Green AM, Mattila JT, Bigbee CL, Bongers KS, Lin PL, Flynn JL. CD4(+) regulatory T cells in a cynomolgus macaque model of Mycobacterium tuberculosis infection. J Infect Dis. 2010; 202: 533-41.

Suchard MS, Mayne E, Green VA, Shalekoff S, Donninger SL, Stevens WS, Gray CM, Tiemessen CT. FOXP3 expression is upregulated in CD4+T cells in progressive HIV-1 infection and is a marker of disease severity. PLoS One. 2010; 5: e11762.

Author biographies is not available.