Joshua C Wallington1, Anthony P Williams2, Karl J Staples3, Tom M A Wilkinson4. 1. Clinical & Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton, United Kingdom. 2. Cancer Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton, United Kingdom; Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom. 3. Clinical & Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton, United Kingdom; Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom. Electronic address: k.staples@southampton.ac.uk. 4. Clinical & Experimental Sciences, University of Southampton Faculty of Medicine, Sir Henry Wellcome Laboratories, Southampton General Hospital, Southampton, United Kingdom; Southampton NIHR Respiratory Biomedical Research Unit, Southampton General Hospital, Southampton, United Kingdom; Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Abstract
BACKGROUND: Bacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity might 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, the role of which in lung immunity is unclear. OBJECTIVE: The aim of this study was to determine the mechanisms behind conventional T-cell 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 cocultured with autologous T cells. Cytotoxic responses of T-cell subsets were measured by using 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 a novel mechanism through 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 might lead to new therapeutic opportunities to modulate the antibacterial response and improve clinical outcome.
BACKGROUND: Bacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity might 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, the role of which in lung immunity is unclear. OBJECTIVE: The aim of this study was to determine the mechanisms behind conventional T-cell 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 cocultured with autologous T cells. Cytotoxic responses of T-cell subsets were measured by using 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 a novel mechanism through 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 might lead to new therapeutic opportunities to modulate the antibacterial response and improve clinical outcome.
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