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

Publication date: Available online 1 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Joshua C. Wallington, Anthony P. Williams, Karl J. Staples, Tom M.A. Wilkinson
BackgroundBacterial 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.ObjectiveThe aim of this study was to determine the mechanisms behind conventional T and MAIT cell cytotoxic responses to NTHi.MethodsHuman 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.ResultsWe 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.ConclusionsOverall 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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Teaser

The mechanisms controlling the cytotoxic response of MAIT cells to NTHi infection are unknown. Our observations provide a new understanding of protective immune mechanisms and also potential new therapeutic opportunities to improve clinical outcome.


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