Skip to main content
Top
Published in: BMC Immunology 1/2018

Open Access 01-12-2018 | Research article

Immune activation and regulatory T cells in Mycobacterium tuberculosis infected lymph nodes

Authors: Karima Sahmoudi, Hassan Abbassi, Nada Bouklata, Mohamed Nouredine El Alami, Abderrahmane Sadak, Christopher Burant, W. Henry Boom, Rajae El Aouad, David H. Canaday, Fouad Seghrouchni

Published in: BMC Immunology | Issue 1/2018

Login to get access

Abstract

Background

Lymph node tuberculosis (LNTB) is the most frequent extrapulmonary form of tuberculosis (TB). Studies of human tuberculosis at sites of disease are limited. LNTB provides a unique opportunity to compare local in situ and peripheral blood immune response in active Mycobacterium tuberculosis (Mtb) disease. The present study analysed T regulatory cells (Treg) frequency and activation along with CD4+ T cell function in lymph nodes from LNTB patients.

Results

Lymph node mononuclear cells (LNMC) were compared to autologous peripheral blood mononuclear cells (PBMC). LNMC were enriched for CD4+ T cells with a late differentiated effector memory phenotype. No differences were noted in the frequency and mutifunctional profile of memory CD4+ T cells specific for Mtb. The proportion of activated CD4+ and Tregs in LNMC was increased compared to PBMC. The correlation between Tregs and activated CD4+ T cells was stronger in LNMC than PBMC. Tregs in LNMC showed a strong positive correlation with Th1 cytokine production (IL2, IFNγ and TNFα) as well as MIP-1α after Mtb antigen stimulation. A subset of Tregs in LNMC co-expressed HLA-DR and CD38, markers of activation.

Conclusion

Further research will determine the functional relationship between Treg and activated CD4+ T cells at lymph node sites of Mtb infection.
Appendix
Available only for authorised users
Literature
1.
go back to reference WHO, Global tuberculosis control: WHO Report 2016. WHO, Global tuberculosis control: WHO Report 2016.
2.
go back to reference Rodrigues DS, Medeiros EA, Weckx LY, Bonnez W, Salomao R, Kallas EG. Immunophenotypic characterization of peripheral T lymphocytes in Mycobacterium tuberculosis infection and disease. Clin Exp Immunol. 2002;128:149–54.CrossRef Rodrigues DS, Medeiros EA, Weckx LY, Bonnez W, Salomao R, Kallas EG. Immunophenotypic characterization of peripheral T lymphocytes in Mycobacterium tuberculosis infection and disease. Clin Exp Immunol. 2002;128:149–54.CrossRef
3.
go back to reference Hertoghe T, Wajja A, Ntambi L, Okwera A, Aziz MA, Hirsch C, Johnson J, Toossi Z, Mugerwa R, Mugyenyi P, Colebunders R, Eller J, Vanham G. T cell activation, apoptosis and cytokine dysregulation in the (co) pathogenesis of HIV and pulmonary tuberculosis (TB). Clin Exp Immunol. 2000;122:350–7.CrossRef Hertoghe T, Wajja A, Ntambi L, Okwera A, Aziz MA, Hirsch C, Johnson J, Toossi Z, Mugerwa R, Mugyenyi P, Colebunders R, Eller J, Vanham G. T cell activation, apoptosis and cytokine dysregulation in the (co) pathogenesis of HIV and pulmonary tuberculosis (TB). Clin Exp Immunol. 2000;122:350–7.CrossRef
7.
go back to reference 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;7:803–10.CrossRef 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;7:803–10.CrossRef
8.
go back to reference 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;4:409–16.CrossRef 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;4:409–16.CrossRef
9.
go back to reference Rodríguez-Perea AL, Arcia ED, Rueda CM, Velilla PA. Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Imm. 2016;185(3):281–91.CrossRef Rodríguez-Perea AL, Arcia ED, Rueda CM, Velilla PA. Phenotypical characterization of regulatory T cells in humans and rodents. Clin Exp Imm. 2016;185(3):281–91.CrossRef
10.
go back to reference Wergeland I, Aßmus J, Dyrhol-Riise AM. T Regulatory Cells and Immune Activation in Mycobacterium tuberculosis Infection and the Effect of Preventive Therapy. Scand J Imm. 2011;73:234–42.CrossRef Wergeland I, Aßmus J, Dyrhol-Riise AM. T Regulatory Cells and Immune Activation in Mycobacterium tuberculosis Infection and the Effect of Preventive Therapy. Scand J Imm. 2011;73:234–42.CrossRef
11.
go back to reference De Almeida AS, Fiske CT, Sterling TR, Kalamsa 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.CrossRef De Almeida AS, Fiske CT, Sterling TR, Kalamsa 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.CrossRef
12.
go back to reference Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53.CrossRef Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53.CrossRef
13.
go back to reference Baecher-Allan C, Wolf E, Hafler DA. Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+ CD25+ T cells. Clin Immunol. 2005;115:10–8.CrossRef Baecher-Allan C, Wolf E, Hafler DA. Functional analysis of highly defined, FACS-isolated populations of human regulatory CD4+ CD25+ T cells. Clin Immunol. 2005;115:10–8.CrossRef
14.
go back to reference Nemeth J, Rumetshofer R, Winkler HM, Burghuber OC, Müller C, Winkler S. Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection. Eur J Immunol. 2012;42(11):2844–50.CrossRef Nemeth J, Rumetshofer R, Winkler HM, Burghuber OC, Müller C, Winkler S. Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection. Eur J Immunol. 2012;42(11):2844–50.CrossRef
15.
go back to reference Diedrich CR, O'Hern J, Gutierrez MG, Allie N, Papier P, Meintjes G, Coussens AK, Wainwright H, Wilkinson RJ. Relationship between HIV Coinfection, Interleukin 10 Production, and Mycobacterium tuberculosis in Human Lymph Node Granulomas. J Infect Dis. 2016;214(9):1309–18.CrossRef Diedrich CR, O'Hern J, Gutierrez MG, Allie N, Papier P, Meintjes G, Coussens AK, Wainwright H, Wilkinson RJ. Relationship between HIV Coinfection, Interleukin 10 Production, and Mycobacterium tuberculosis in Human Lymph Node Granulomas. J Infect Dis. 2016;214(9):1309–18.CrossRef
16.
go back to reference Wang T, Lv M, Qian Q, Nie Y, Yu L, Hou Y. Increased frequencies of T helper type 17 cells in tuberculous pleural effusion. Tuberculosis. 2011;91:231–7.CrossRef Wang T, Lv M, Qian Q, Nie Y, Yu L, Hou Y. Increased frequencies of T helper type 17 cells in tuberculous pleural effusion. Tuberculosis. 2011;91:231–7.CrossRef
17.
go back to reference Rumetshofer R, Winkler HM, Burghuber OC, Müller C, Winkler S. Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection. Eur J Immunol. 2012;42(11):2844–50.CrossRef Rumetshofer R, Winkler HM, Burghuber OC, Müller C, Winkler S. Active tuberculosis is characterized by an antigen specific and strictly localized expansion of effector T cells at the site of infection. Eur J Immunol. 2012;42(11):2844–50.CrossRef
18.
go back to reference El Fenniri L, Toossi Z, Aung H, El Iraki G, Bourkkadi J, Benamor J, Laskri A, Berrada N, Benjouad A, Mayanja-Kizza H, Betts MR, El Aouad R, Canaday DH. Polyfunctional mycobacterium tuberculosis-specific effector memory CD4+ T cells at sites of pleural TB. Tuberculosis. 2011;91:224–30.CrossRef El Fenniri L, Toossi Z, Aung H, El Iraki G, Bourkkadi J, Benamor J, Laskri A, Berrada N, Benjouad A, Mayanja-Kizza H, Betts MR, El Aouad R, Canaday DH. Polyfunctional mycobacterium tuberculosis-specific effector memory CD4+ T cells at sites of pleural TB. Tuberculosis. 2011;91:224–30.CrossRef
19.
go back to reference Chiacchio T, Petruccioli E, Vanini V, Butera O, Cuzzi G, Petrone L, Matteucci G, Lauria FN, Franken KL, Girardi E, Ottenhoff TH, Goletti D. Higher Frequency of T-Cell Response to M. tuberculosis Latency Antigen Rv2628 at the Site of Active Tuberculosis Disease than in Peripheral Blood. PlosOne. 2011;6:e27539. https://doi.org/10.1371/journal.pone.0027539.CrossRef Chiacchio T, Petruccioli E, Vanini V, Butera O, Cuzzi G, Petrone L, Matteucci G, Lauria FN, Franken KL, Girardi E, Ottenhoff TH, Goletti D. Higher Frequency of T-Cell Response to M. tuberculosis Latency Antigen Rv2628 at the Site of Active Tuberculosis Disease than in Peripheral Blood. PlosOne. 2011;6:e27539. https://​doi.​org/​10.​1371/​journal.​pone.​0027539.CrossRef
20.
go back to reference Kumar NP, Sridhar R, Banurekha VV, Nair D, Jawahar MS, Nutman TB, Babu S. Expansion of Pathogen-Specific Mono- and Multifunctional Th1 and Th17 Cells in Multi-Focal Tuberculous Lymphadenitis. PlosOne. 2013;8(2):e57123.CrossRef Kumar NP, Sridhar R, Banurekha VV, Nair D, Jawahar MS, Nutman TB, Babu S. Expansion of Pathogen-Specific Mono- and Multifunctional Th1 and Th17 Cells in Multi-Focal Tuberculous Lymphadenitis. PlosOne. 2013;8(2):e57123.CrossRef
21.
go back to reference Marín ND, Paris SC, Rojas M, Garcia LF. Functional profile of CD4+ and CD8+ T cells in latently infected individuals and patients with active TB. Tuberculosis. 2013;93:155–66.CrossRef Marín ND, Paris SC, Rojas M, Garcia LF. Functional profile of CD4+ and CD8+ T cells in latently infected individuals and patients with active TB. Tuberculosis. 2013;93:155–66.CrossRef
22.
go back to reference 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;39:723–9.CrossRef 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;39:723–9.CrossRef
23.
go back to reference Caccamo N, Guggino G, Joosten SA, Gelsomino G, Di Carlo P, Titone L, Galati D, Bocchino M, Matarese A, Salerno A, Sanduzzi A, Franken WP, Ottenhoff TH, Dieli F. Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection. Eur J Immunol. 2010;40:2211–20.CrossRef Caccamo N, Guggino G, Joosten SA, Gelsomino G, Di Carlo P, Titone L, Galati D, Bocchino M, Matarese A, Salerno A, Sanduzzi A, Franken WP, Ottenhoff TH, Dieli F. Multifunctional CD4(+) T cells correlate with active Mycobacterium tuberculosis infection. Eur J Immunol. 2010;40:2211–20.CrossRef
24.
go back to reference Adekambi T, Ibegbu CC, Cagle S, Kalokhe AS, Wang YF, Hu Y, Day CL, Ray SM, Rengarajan J. Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response. J Clin Invest. 2015;125:1827–38.CrossRef Adekambi T, Ibegbu CC, Cagle S, Kalokhe AS, Wang YF, Hu Y, Day CL, Ray SM, Rengarajan J. Biomarkers on patient T cells diagnose active tuberculosis and monitor treatment response. J Clin Invest. 2015;125:1827–38.CrossRef
25.
go back to reference Wilkinson KA, Wilkinson RJ, Pathan A, Ewer K, Prakash M, Klenerman P, Maskell N, Davies R, Pasvol G, Lalvani A. Ex vivo characterization of early secretory antigenic target 6–specific T cells at sites of active disease in pleural tuberculosis. Clin Infect Dis. 2005;40:184–7.CrossRef Wilkinson KA, Wilkinson RJ, Pathan A, Ewer K, Prakash M, Klenerman P, Maskell N, Davies R, Pasvol G, Lalvani A. Ex vivo characterization of early secretory antigenic target 6–specific T cells at sites of active disease in pleural tuberculosis. Clin Infect Dis. 2005;40:184–7.CrossRef
26.
go back to reference Nemeth J, Winkler HM, Zwick RH, Rumetshofer R, Schenk P, Burghuber OC, Graninger W, Ramharter M, Winkler S. Recruitment of Mycobacterium tuberculosis specific CD41 T cells to the site of infection for diagnosis of active tuberculosis. J Intern Med. 2009;265:163–8.CrossRef Nemeth J, Winkler HM, Zwick RH, Rumetshofer R, Schenk P, Burghuber OC, Graninger W, Ramharter M, Winkler S. Recruitment of Mycobacterium tuberculosis specific CD41 T cells to the site of infection for diagnosis of active tuberculosis. J Intern Med. 2009;265:163–8.CrossRef
27.
go back to reference 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.CrossRef 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.CrossRef
28.
go back to reference Baecher-Allan C, Wolf E, Hafler DA. MHC Class II Expression Identifies Functionally Distinct Human Regulatory T Cells. J Immunol. 2006;176:4622–463.CrossRef Baecher-Allan C, Wolf E, Hafler DA. MHC Class II Expression Identifies Functionally Distinct Human Regulatory T Cells. J Immunol. 2006;176:4622–463.CrossRef
30.
go back to reference Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, Pritchard GH, Silver JS, Bouladoux N, Stumhofer JS, Harris TH, Grainger J, Wojno ED, Wagage S, Roos DS, Scott P, Turka LA, Cherry S, Reiner SL, Cua D, Belkaid Y, Elloso MM, Hunter CA. The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology. Immunity. 2012;37(3):511–23. https://doi.org/10.1016/j.immuni.2012.06.014.CrossRefPubMedPubMedCentral Hall AO, Beiting DP, Tato C, John B, Oldenhove G, Lombana CG, Pritchard GH, Silver JS, Bouladoux N, Stumhofer JS, Harris TH, Grainger J, Wojno ED, Wagage S, Roos DS, Scott P, Turka LA, Cherry S, Reiner SL, Cua D, Belkaid Y, Elloso MM, Hunter CA. The cytokines interleukin 27 and interferon-γ promote distinct Treg cell populations required to limit infection-induced pathology. Immunity. 2012;37(3):511–23. https://​doi.​org/​10.​1016/​j.​immuni.​2012.​06.​014.CrossRefPubMedPubMedCentral
Metadata
Title
Immune activation and regulatory T cells in Mycobacterium tuberculosis infected lymph nodes
Authors
Karima Sahmoudi
Hassan Abbassi
Nada Bouklata
Mohamed Nouredine El Alami
Abderrahmane Sadak
Christopher Burant
W. Henry Boom
Rajae El Aouad
David H. Canaday
Fouad Seghrouchni
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2018
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-018-0266-8

Other articles of this Issue 1/2018

BMC Immunology 1/2018 Go to the issue