Abstract
Lymphocytes are crucial for protecting the body against infectious diseases. T cells are a diverse group of lymphocytes with many distinct functions. Mucosal-associated invariant T (MAIT) cells are a subset of unconventional T lymphocytes, distinguished by their semi-invariant T cell receptor (TCR) α chain and dependence on the nonpolymorphic class Ib MHC molecule, MR1. MR1 presents antigens derived from microbial riboflavin synthesis. MAIT cells are enriched in the blood and mucosal tissues; in humans they are found in the highest frequencies in the blood and liver. In humans MAIT cells range from 1-10% of αβT cells, but in mice they regularly make up less than 1% of T cells. MAIT cells exhibit a memory-like phenotype and possess preprogrammed effector functions that enable them to perform a wide range of immune responses, from antimicrobial defence to metabolic regulation and tissue repair. MAIT cells can be activated in two main ways: MR1/TCR-dependent activation, together with costimulation via CD28, TLR agonists, or the cytokines interleukin-12 (IL-12) and IL-18; TCR independent activation, by IL-12 and IL-18 alone or in combination with Type 1 interferons (T1-IFNs), such as IFN-α and IFN-β. T1 IFNs have been identified as important contributors to cytokine-mediated MAIT cell activation and as a costimulatory signal in TCR dependent activation in vitro but their effect has not been assessed in vivo. Therefore, this study sought to confirm the role of T1 IFNs on costimulation in humans in vitro and determine the effect of T1 IFNs on MAIT cell activation in a mouse model of bacterial infection. Using human peripheral blood mononuclear cells, the costimulatory role of T1 IFNs in TCR mediated activation of MAIT cells was confirmed; enhanced activation and effector functions were found in MAIT cells treated with T1 IFNs and the MAIT activating ligand 5-OP-RU, compared to 5-OP-RU alone. To understand the contribution of T1 IFNs in TCR-mediated MAIT cell activation in vivo, a murine model of BCG lung infection was used. MAIT cells were present in the lung and were activated during BCG infection. When T1 IFNs signalling was blocked during BCG lung infection the number of MAIT cells was greatly reduced and the phenotype was altered. The results of this thesis suggests an important role for T1 IFNs in MAIT cell proliferation and phenotype during pulmonary BCG infection in vivo. However, repeated models and further research are needed to fully understand the role of MAIT cells during BCG infection and the effect of T1 IFNs in their response.