Lung resident memory CD8+ T cells during viral infections - generation and functionality regulated by localisation and type I IFNs

According to the World Health Organisation, lung infections kill ~3 million people each year, more than twice the number that die of diarrhoeal diseases, AIDS and diabetes combined. Viruses are responsible for many of these infections, but there is relatively little research investment in discovering how upper respiratory viral infections spread to the lungs and cause pneumonia.

The most common viral causes of lower respiratory tract infections are respiratory syncytial virus (RSV) and influenza A virus (IAV), both frequently causing severe disease. Despite a vast effort over six decades, vaccines that elicit protection against RSV are yet to be developed. There are partially effective vaccines against IAV, but they need to be redesigned each year to match the new strains of IAV that constantly evolve.

Most vaccines are given as an injection and induce protective antibodies that circulate in the bloodstream. As such, they are not optimised to specifically protect the lung or to mobilise lung-resident immune cells that help protect from severe disease.

Our understanding of how lung-resident immune cells defend us against respiratory viruses is incomplete, but recent evidence shows that a special subset of T cells, known as tissue resident memory T (Trm) cells, are critical for rapid elimination of viruses such as RSV and IAV. While it is likely that the environment in which these cells reside shapes their function and life span, it remains unclear how this happens.

We believe that Trm cells are maintained in specific niches within the lung where they are nurtured by interactions with neighbouring cells.

During viral infection, essential anti-viral molecules called type I interferons (IFNs) are produced in large quantities. These cytokines can alter how T cells behave but their role in determining the function of Trm cells is not known. In this proposal we will study how type I IFNs affect the behaviour of Trm cells.

To achieve this, we will use a new technique in which we study live slices of lung tissue in culture. These living slices can be re-stimulated with virus or components of the virus in the lab to enable detailed visualisation of tissue-resident cells and their responses. We will compare slices from mice and humans, investigating how type I IFNs influence Trm cells; their survival, function and localisation.

Thus, this proposal will provide increased understanding of how tissue-protective T cells are regulated, which will help the development of new vaccines and treatments that harness the potentials of Trm cells to alleviate viral induced disease.