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IL-12 and IL-7 synergise to control MAIT cell cytotoxic responses to bacterial infection

IL-12 and IL-7 synergise to control MAIT cell cytotoxic responses to bacterial infection
IL-12 and IL-7 synergise to control MAIT cell cytotoxic responses to bacterial infection
Background
Bacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity may be key to controlling infection, but the responses of NTHi-specific T cell populations are not well understood. Mucosal-associated invariant T (MAIT) cells are a recently-discovered, innate-like subset of T cells with cytotoxic function, whose role in lung immunity is unclear.
Objective
The aim of this study was to determine the mechanisms behind conventional T and MAIT cell cytotoxic responses to NTHi.
Methods
Human ex vivo lung explants were infected with a clinical strain of NTHi. Monocyte-derived macrophages were also infected with NTHi in vitro and co-cultured with autologous T cells. Cytotoxic responses of T cell subsets were measured by flow cytometry.
Results
We found significant upregulation of the cytotoxic markers, CD107a and granzyme B, in lung CD4+, CD8+ and MAIT cell populations. We show that MAIT cell cytotoxic responses were upregulated by a combination of both time-dependent antigen presentation and through a novel mechanism by which IL-12 and IL-7 synergistically control granzyme B through upregulation of the IL-12 receptor.
Conclusions
Overall our data provide evidence for a cytotoxic role of MAIT cells in the lung and highlight important differences in the control of adaptive and innate-like T cell responses. Understanding these mechanisms may lead to new therapeutic opportunities to modulate the anti-bacterial response and improve clinical outcome.
0091-6749
Wallington, Joshua C.
7f2909e0-96f1-4237-b2c2-ea3aa695a9d1
Williams, Anthony P.
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Tom MA
8c55ebbb-e547-445c-95a1-c8bed02dd652
Wallington, Joshua C.
7f2909e0-96f1-4237-b2c2-ea3aa695a9d1
Williams, Anthony P.
973ff46f-46f1-4d7c-b27d-0f53221e4c44
Staples, Karl J.
e0e9d80f-0aed-435f-bd75-0c8818491fee
Wilkinson, Tom MA
8c55ebbb-e547-445c-95a1-c8bed02dd652

Wallington, Joshua C., Williams, Anthony P., Staples, Karl J. and Wilkinson, Tom MA (2017) IL-12 and IL-7 synergise to control MAIT cell cytotoxic responses to bacterial infection. Journal of Allergy and Clinical Immunology. (doi:10.1016/j.jaci.2017.08.009).

Record type: Article

Abstract

Background
Bacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity may be key to controlling infection, but the responses of NTHi-specific T cell populations are not well understood. Mucosal-associated invariant T (MAIT) cells are a recently-discovered, innate-like subset of T cells with cytotoxic function, whose role in lung immunity is unclear.
Objective
The aim of this study was to determine the mechanisms behind conventional T and MAIT cell cytotoxic responses to NTHi.
Methods
Human ex vivo lung explants were infected with a clinical strain of NTHi. Monocyte-derived macrophages were also infected with NTHi in vitro and co-cultured with autologous T cells. Cytotoxic responses of T cell subsets were measured by flow cytometry.
Results
We found significant upregulation of the cytotoxic markers, CD107a and granzyme B, in lung CD4+, CD8+ and MAIT cell populations. We show that MAIT cell cytotoxic responses were upregulated by a combination of both time-dependent antigen presentation and through a novel mechanism by which IL-12 and IL-7 synergistically control granzyme B through upregulation of the IL-12 receptor.
Conclusions
Overall our data provide evidence for a cytotoxic role of MAIT cells in the lung and highlight important differences in the control of adaptive and innate-like T cell responses. Understanding these mechanisms may lead to new therapeutic opportunities to modulate the anti-bacterial response and improve clinical outcome.

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Accepted/In Press date: 21 August 2017
e-pub ahead of print date: 1 September 2017

Identifiers

Local EPrints ID: 413796
URI: https://eprints.soton.ac.uk/id/eprint/413796
ISSN: 0091-6749
PURE UUID: 3beb3644-ba93-4b70-ba21-c46e017b06fc
ORCID for Karl J. Staples: ORCID iD orcid.org/0000-0003-3844-6457

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Date deposited: 06 Sep 2017 16:31
Last modified: 03 Dec 2019 05:52

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