Aim: to discover the immunological consequences of activation of a novel tissue-repair programme in mucosal associated invariant T (MAIT) cells in the lung, and its potential for therapeutic manipulation using MAIT cell ligands.
MAIT cells are an intriguing, novel, innate-like T cell subset which are highly conserved in evolution, are abundant in the lungs and are capable of sensing a wide range of microbial pathogens. Our studies have extended the range of known capabilities of MAIT cells to include protection against respiratory viruses, and, most recently, a previously unsuspected role in promoting tissue repair. Accurate regulation of tissue repair is essential for restoration of homeostasis and organ function after acute lung injury, whilst its dysregulation can lead to irreversible fibrosis.
We believe MAIT cells contribute to recovery after acute viral pneumonia or sterile acute lung injury, and that their function can be enhanced by stimulation with synthetic MAIT cell ligands.
We will test these hypotheses both in vivo using murine models of influenza virus infection and LPS-induced acute lung injury, and also in vivo using human air-liquid interface tissue repair studies.
The DPhil candidate will acquire expertise in cellular immunology, using murine models of human disease, in vitro human air-liquid interface culture, cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), multiparameter flow-cytometry, IncuCyte wound migration studies, chip cytometry, immunofluorescent fluorescent imaging and microbiological techniques
Project reference number: 1032
|Timothy Hinks BMBCh MA (Cantab) MRCP PhD||Experimental Medicine Division||Oxford University, John Radcliffe Hospital||GBRfirstname.lastname@example.org|
|Paul Klenerman||Experimental Medicine Division||Oxford University, Peter Medawar Building||GBRemail@example.com|
Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T cells, expressing a semi-invariant T-cell receptor (TCR) and able to recognize small molecules presented on the non-polymorphic MHC-related protein 1. Their intrinsic effector-memory phenotype, enabling secretion of pro-inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune-mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation-induced down-regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR-independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers. Hide abstract
Mucosal associated invariant T (MAIT) cells recognise conserved microbial metabolites from riboflavin synthesis. Striking evolutionary conservation and pulmonary abundance implicate them in antibacterial host defence, yet their functions in protection against clinically important pathogens are unknown. Here we show that mouse Legionella longbeachae infection induces MR1-dependent MAIT cell activation and rapid pulmonary accumulation of MAIT cells associated with immune protection detectable in immunocompetent host animals. MAIT cell protection is more evident in mice lacking CD4 cells, and adoptive transfer of MAIT cells rescues immunodeficient Rag2γC mice from lethal Legionella infection. Protection is dependent on MR1, IFN-γ and GM-CSF, but not IL-17A, TNF or perforin, and enhanced protection is detected earlier after infection of mice antigen-primed to boost MAIT cell numbers before infection. Our findings define a function for MAIT cells in protection against a major human pathogen and indicate a potential role for vaccination to enhance MAIT cell immunity. Hide abstract
Mucosal associated invariant T (MAIT) cells are evolutionarily-conserved, innate-like lymphocytes which are abundant in human lungs and can contribute to protection against pulmonary bacterial infection. MAIT cells are also activated during human viral infections, yet it remains unknown whether MAIT cells play a significant protective or even detrimental role during viral infections in vivo. Using murine experimental challenge with two strains of influenza A virus, we show that MAIT cells accumulate and are activated early in infection, with upregulation of CD25, CD69 and Granzyme B, peaking at 5 days post-infection. Activation is modulated via cytokines independently of MR1. MAIT cell-deficient MR1 mice show enhanced weight loss and mortality to severe (H1N1) influenza. This is ameliorated by prior adoptive transfer of pulmonary MAIT cells in both immunocompetent and immunodeficient RAG2γC mice. Thus, MAIT cells contribute to protection during respiratory viral infections, and constitute a potential target for therapeutic manipulation. Hide abstract