Regulatory T Cells and Pro-inflammatory Responses Predominate in children with Tuberculosis

被引:19
作者
Whittaker, Elizabeth [1 ,2 ]
Nicol, Mark [2 ]
Zar, Heather J. [3 ,4 ]
Kampmann, Beate [1 ,5 ]
机构
[1] Imperial Coll London, Acad Dept Paediat, London, England
[2] Inst Infect Dis & Mol Med, UCT Fac Hlth Sci, Div Med Microbiol, Dept Clin Lab Sci, Cape Town, South Africa
[3] Univ Cape Town, MRC Unit Child & Adolescent Hlth, Cape Town, South Africa
[4] Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Cape Town, South Africa
[5] MRC Unit Gambia, Vaccines & Immun Theme, Fajara, Gambia
来源
FRONTIERS IN IMMUNOLOGY | 2017年 / 8卷
基金
英国医学研究理事会; 新加坡国家研究基金会; 英国惠康基金;
关键词
tuberculosis; extrapulmonary; pediatric; mycobacterial immunity; regulatory T cells; ACTIVE PULMONARY TUBERCULOSIS; CALMETTE-GUERIN VACCINATION; MYCOBACTERIUM-BOVIS BCG; EXTRAPULMONARY TUBERCULOSIS; INTERFERON-GAMMA; IMMUNE-RESPONSE; IFN-GAMMA; CYTOKINE; DISEASE; BLOOD;
D O I
10.3389/fimmu.2017.00448
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: Following infection with Mycobacterium tuberculosis (M.tb), children are more susceptible to develop disease particularly extrapulmonary disease than adults. The exact mechanisms required for containment of M.tb are not known, but would be important to identify correlates of protection. Objective: To comprehensively analyze key immune responses to mycobacteria between HIV-negative children with extrapulmonary TB (EPTB) compared to children with pulmonary TB (PTB) or healthy controls. Methods: Whole blood was stimulated in vitro with mycobacteria for 24 h or 6 days to induce effector and memory responses. CD4, CD8,gamma delta, regulatory T cells, and their related cytokines were measured. Samples of children with tuberculosis (TB) disease were analyzed both at time of diagnosis and at the end of TB treatment to determine if any differences were due to TB disease or an underlying host phenotype. Results: Seventy-six children with TB disease (48 with PTB and 28 with EPTB) and 83 healthy controls were recruited to the study. The frequency of CD4(+) CD25(+) CD39(+) FOXP3(+) regulatory T cells and secreted IL10 were significantly higher in children with TB compared to healthy controls. IFN gamma-, IL17-, and IL22-producing gamma delta T cells, IL22-producing CD4(+) T cells and secreted pro-inflammatory cytokines (IFN gamma, IL1 beta, and TNF alpha) were significantly lower in children with TB disease compared to healthy controls. IFN gamma- producing CD4(+) T cells and Ki67(+)-proliferating CD4(+) T cells, however, were present in equal numbers in both groups. Following treatment, these immune parameters recovered to "healthy" levels or greater in children with PTB, but not those with extrapulmonary TB. Conclusion: In children with TB disease, a predominantly immune regulatory state is present. These immune findings do not distinguish between children with PTB and EPTB at the time of diagnosis. Following treatment, these inflammatory responses recover in PTB, suggesting that the effect is disease specific rather than due to an underlying host defect.
引用
收藏
页数:11
相关论文
共 41 条
[21]   Suppressed Type 1, Type 2, and Type 17 Cytokine Responses in Active Tuberculosis in Children [J].
Kumar, N. Pavan ;
Anuradha, R. ;
Suresh, R. ;
Ganesh, R. ;
Shankar, Janani ;
Kumaraswami, V. ;
Nutman, Thomas B. ;
Babu, Subash .
CLINICAL AND VACCINE IMMUNOLOGY, 2011, 18 (11) :1856-1864
[22]   Childhood Tuberculosis: Epidemiology and Natural History of Disease [J].
Marais, Ben J. .
INDIAN JOURNAL OF PEDIATRICS, 2011, 78 (03) :321-327
[23]   Predominance of interleukin-22 over interleukin-17 at the site of disease in human tuberculosis [J].
Matthews, Kerryn ;
Wilkinson, Katalin A. ;
Kalsdorf, Barbara ;
Roberts, Teri ;
Diacon, Andreas ;
Walzl, Gerhard ;
Wolske, Janine ;
Ntsekhe, Mpiko ;
Syed, Faisal ;
Russell, James ;
Mayosi, Bongani M. ;
Dawson, Rodney ;
Dheda, Keertan ;
Wilkinson, Robert J. ;
Hanekom, Willem A. ;
Scriba, Thomas J. .
TUBERCULOSIS, 2011, 91 (06) :587-593
[24]   Functional Delineation and Differentiation Dynamics of Human CD4+ T Cells Expressing the FoxP3 Transcription Factor [J].
Miyara, Makoto ;
Yoshioka, Yumiko ;
Kitoh, Akihiko ;
Shima, Tomoko ;
Wing, Kajsa ;
Niwa, Akira ;
Parizot, Christophe ;
Taflin, Cecile ;
Heike, Toshio ;
Valeyre, Dominique ;
Mathian, Alexis ;
Nakahata, Tatsutoshi ;
Yamaguchi, Tomoyuki ;
Nomura, Takashi ;
Ono, Masahiro ;
Amoura, Zahir ;
Gorochov, Guy ;
Sakaguchi, Shimon .
IMMUNITY, 2009, 30 (06) :899-911
[25]   Interleukin 17-producing γδ T cells increased in patients with active pulmonary tuberculosis [J].
Peng, Meiyu ;
Wang, Zhaohua ;
Yao, Chunyan ;
Jiang, Lina ;
Jin, Qili ;
Wang, Jing ;
Li, Baiqing .
CELLULAR & MOLECULAR IMMUNOLOGY, 2008, 5 (03) :203-208
[26]   In Vitro Levels of Interleukin 10 (IL-10) and IL-12 in Response to a Recombinant 32-Kilodalton Antigen of Mycobacterium bovis BCG after Treatment for Tuberculosis [J].
Priya, V. Hari Sai ;
Anuradha, B. ;
Gaddam, Suman Latha ;
Hasnain, Seyed E. ;
Murthy, K. J. R. ;
Valluri, Vijaya Lakshmi .
CLINICAL AND VACCINE IMMUNOLOGY, 2009, 16 (01) :111-115
[27]   Current understanding of the immune response to tuberculosis in children [J].
Roy, Robindra Basu ;
Whittaker, Elizabeth ;
Kampmann, Beate .
CURRENT OPINION IN INFECTIOUS DISEASES, 2012, 25 (03) :250-257
[28]   Distinct, specific IL-17- and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response [J].
Scriba, Thomas J. ;
Kalsdorf, Barbara ;
Abrahams, Deborah-Ann ;
Isaacs, Fatima ;
Hofmeister, Jessica ;
Black, Gillian ;
Hassan, Hisham Y. ;
Wilkinson, Robert J. ;
Walzl, Gerhard ;
Gelderbloem, Sebastian J. ;
Mahomed, Hassan ;
Hussey, Gregory D. ;
Hanekom, Willem A. .
JOURNAL OF IMMUNOLOGY, 2008, 180 (03) :1962-1970
[29]   Cytokine polarization in miliary and pleural tuberculosis [J].
Sharma, SK ;
Mitra, DK ;
Balamurugan, A ;
Pandey, RM ;
Mehra, NK .
JOURNAL OF CLINICAL IMMUNOLOGY, 2002, 22 (06) :345-352
[30]   Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation [J].
Soares, Andreia ;
Govender, Lerisa ;
Hughes, Jane ;
Mavakla, Wendy ;
de Kock, Marwou ;
Barnard, Charlene ;
Pienaar, Bernadette ;
van Rensburg, Esme Janse ;
Jacobs, Gail ;
Khomba, Gloria ;
Stone, Lynnette ;
Abel, Brian ;
Scriba, Thomas J. ;
Hanekom, Willem A. .
JOURNAL OF IMMUNOLOGICAL METHODS, 2010, 362 (1-2) :43-50