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Mycobacteria-specific mono- and polyfunctional CD4+ T cell profiles in children with latent and active tuberculosis: a prospective proof-of-concept study

Mycobacteria-specific mono- and polyfunctional CD4+ T cell profiles in children with latent and active tuberculosis: a prospective proof-of-concept study
Mycobacteria-specific mono- and polyfunctional CD4+ T cell profiles in children with latent and active tuberculosis: a prospective proof-of-concept study

Background: Current immune-based TB tests, including the tuberculin skin test (TST) and interferon-gamma release assays (IGRA), have significant limitations, including the inability to distinguish between latent TB infection (LTBI) and active TB. Few biomarkers with the potential to discriminate between these two infection states have been identified. Objective: To determine whether functional profiling of mycobacteria-specific T cells can distinguish between TB-infected and -uninfected children, and simultaneously discriminate between LTBI and active TB. Methods: One hundred and forty-nine children with suspected active TB or risk factors for LTBI were recruited at the Royal Children's Hospital Melbourne. Whole-blood stimulation assays, using ESAT-6, CFP-10, PPD, and heat-killed M. tuberculosis as stimulants, were done, followed by intracellular cytokine staining and flow cytometric analysis. Results: Eighty-two participants in the well-defined diagnostic categories ‘uninfected individuals’ (asymptomatic, TST 0 mm / IGRA-; n = 61), LTBI (asymptomatic, TST ≥10 mm / IGRA+, normal chest radiograph; n = 15), or active TB [microbiologically-confirmed (n = 3) or fulfilling stringent criteria (n = 3)] were included in the final analysis. The proportions of mycobacteria-specific single-positive TNF-α+ and double-positive IFN-γ+/TNF-α+ CD4+ T cells were significantly higher in participants with active TB than in those with LTBI and uninfected individuals. Additionally, the frequency of IL-17-expressing CD4+ T cells, predominately with single-positive IL-17+ and double-positive IL-2+/IL-17+ phenotypes, was higher in participants with active TB than in the other two groups. Conclusions: The frequencies and functional profiles of mycobacteria-specific CD4+ T cells differ significantly both between TB-infected and TB-uninfected children, and between LTBI and active TB. Although confirmation in further studies will be required, these findings indicate that functional profiling of mycobacteria-specific CD4+ T cells could potentially be exploited for novel immune-based TB assays that enable the distinction between infection states based on a blood sample alone.

Child, Diagnosis, Functional profile, Immunoassay, T cell, Tuberculosis
1664-3224
Tebruegge, Marc
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Ritz, Nicole
ce6604a1-f373-4d76-838a-1ae75f35b20b
Donath, Susan
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Dutta, Binita
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Forbes, Benjamin
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Clifford, Vanessa
bf6063da-16e9-4b72-b4e7-ba2582ac3eb5
Zufferey, Christel
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De Rose, Robert
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Robins-Browne, Roy M.
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Hanekom, Willem
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Graham, Stephen M.
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Connell, Tom
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Curtis, Nigel
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Tebruegge, Marc
2c3dff22-0b5f-48a7-bb36-ce323705f74a
Ritz, Nicole
ce6604a1-f373-4d76-838a-1ae75f35b20b
Donath, Susan
b1bb69fe-e708-4ec5-b98a-6bdab36e71b1
Dutta, Binita
0621b33e-ae04-427c-ac38-ab40db51174a
Forbes, Benjamin
5a92eda9-33a1-4038-aaed-58ff19b936e4
Clifford, Vanessa
bf6063da-16e9-4b72-b4e7-ba2582ac3eb5
Zufferey, Christel
5df305e6-0080-4e35-9c70-5fd8006b4740
De Rose, Robert
a9e3b428-658c-4a40-a1ce-c0e5634874e6
Robins-Browne, Roy M.
9014298a-6452-4be4-b6fa-487003e67fef
Hanekom, Willem
c9ec155b-a8ad-49a2-baf2-f8996b43baf9
Graham, Stephen M.
415ae6e5-9615-4883-b745-29c5da244e21
Connell, Tom
7c1afb37-45bd-44a3-a274-20839e68f2c3
Curtis, Nigel
60e08f70-7ce9-42b3-8074-d5df55131b12

Tebruegge, Marc, Ritz, Nicole, Donath, Susan, Dutta, Binita, Forbes, Benjamin, Clifford, Vanessa, Zufferey, Christel, De Rose, Robert, Robins-Browne, Roy M., Hanekom, Willem, Graham, Stephen M., Connell, Tom and Curtis, Nigel (2019) Mycobacteria-specific mono- and polyfunctional CD4+ T cell profiles in children with latent and active tuberculosis: a prospective proof-of-concept study. Frontiers in Immunology, 10 (APR). (doi:10.3389/fimmu.2019.00431).

Record type: Article

Abstract

Background: Current immune-based TB tests, including the tuberculin skin test (TST) and interferon-gamma release assays (IGRA), have significant limitations, including the inability to distinguish between latent TB infection (LTBI) and active TB. Few biomarkers with the potential to discriminate between these two infection states have been identified. Objective: To determine whether functional profiling of mycobacteria-specific T cells can distinguish between TB-infected and -uninfected children, and simultaneously discriminate between LTBI and active TB. Methods: One hundred and forty-nine children with suspected active TB or risk factors for LTBI were recruited at the Royal Children's Hospital Melbourne. Whole-blood stimulation assays, using ESAT-6, CFP-10, PPD, and heat-killed M. tuberculosis as stimulants, were done, followed by intracellular cytokine staining and flow cytometric analysis. Results: Eighty-two participants in the well-defined diagnostic categories ‘uninfected individuals’ (asymptomatic, TST 0 mm / IGRA-; n = 61), LTBI (asymptomatic, TST ≥10 mm / IGRA+, normal chest radiograph; n = 15), or active TB [microbiologically-confirmed (n = 3) or fulfilling stringent criteria (n = 3)] were included in the final analysis. The proportions of mycobacteria-specific single-positive TNF-α+ and double-positive IFN-γ+/TNF-α+ CD4+ T cells were significantly higher in participants with active TB than in those with LTBI and uninfected individuals. Additionally, the frequency of IL-17-expressing CD4+ T cells, predominately with single-positive IL-17+ and double-positive IL-2+/IL-17+ phenotypes, was higher in participants with active TB than in the other two groups. Conclusions: The frequencies and functional profiles of mycobacteria-specific CD4+ T cells differ significantly both between TB-infected and TB-uninfected children, and between LTBI and active TB. Although confirmation in further studies will be required, these findings indicate that functional profiling of mycobacteria-specific CD4+ T cells could potentially be exploited for novel immune-based TB assays that enable the distinction between infection states based on a blood sample alone.

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Accepted/In Press date: 18 February 2019
Published date: 5 April 2019
Keywords: Child, Diagnosis, Functional profile, Immunoassay, T cell, Tuberculosis

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Local EPrints ID: 432057
URI: https://eprints.soton.ac.uk/id/eprint/432057
ISSN: 1664-3224
PURE UUID: 8aca2686-bfc0-45e0-b2ca-6d0ed67d69eb

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Date deposited: 28 Jun 2019 16:30
Last modified: 19 Jul 2019 16:31

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Contributors

Author: Marc Tebruegge
Author: Nicole Ritz
Author: Susan Donath
Author: Binita Dutta
Author: Benjamin Forbes
Author: Vanessa Clifford
Author: Christel Zufferey
Author: Robert De Rose
Author: Roy M. Robins-Browne
Author: Willem Hanekom
Author: Stephen M. Graham
Author: Tom Connell
Author: Nigel Curtis

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