IL-12 and IL-7 synergize to control mucosal-associated invariant T-cell cytotoxic responses to bacterial infection

Abstract

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. The aim of this study was to determine the mechanisms behind conventional T-cell and MAIT cell cytotoxic responses to NTHi. Human exvivo lung explants were infected with a clinical strain of NTHi. Monocyte-derived macrophages were also infected with NTHi invitro and cocultured with autologous T cells. Cytotoxic responses of T-cell subsets were measured by using flow cytometry. 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. 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.