Initial Research Proposal

‘The role of γδ T cells in immunity against Mycobacterium tuberculosis’

Tuberculosis (TB) is a major global public health issue. According to the 2019 global tuberculosis report it remains amongst the top 10 killers worldwide and the leading cause of death from a single infectious agent. About one quarter of the world’s population is infected with Mycobacterium tuberculosis (Mtb- the causative agent of TB) so developing a treatment is vital in prevention of a TB epidemic. The burden it brings on people ranges from fatigue, chest pain to lung scarring and death. The antibiotic rifampicin is a commonly used drug for treatment, but emerging multi-drug-resistant Mtb (MDR-MTB) strains are unaffected by this and successfully thrive with almost 558,000 new cases yearly since 2017. The only licenced vaccine against Mtb, Bacillus-Calmette-Guérin (BCG), has saved many children’s lives, but does not protect against pulmonary TB in adults. These statistics indicate the urgent need for a different perspective when developing treatments and therapies against TB.

We propose to investigate the treatment potential of a class of white blood cells termed γδ T cells for tuberculosis in vitro. We know that immunity against Mtb requires the action of macrophages in the lung that work by phagocytosis (engulfing and killing bacteria). These macrophages are controlled by T cells. We know that Mtb-specific-CD4⁺T cells release proteins that promote macrophage activation. These proteins are also secreted by a population of ‘innate T cells’ that recognise patterns of products released by Mtb in an unconventional manner. The cells that we want to investigate, γδ T cells are a type of innate T cells that recognise Mtb and Mtb products.

While we know that γδ T cells, can directly recognise and respond to Mtb, it is not known if and how these cells protect against Mtb infection. We hypothesise that γδ T cells can recognise Mtb-infected macrophages and can promote killing of the bacteria by the macrophages. We propose to find out if individual subsets of γδ T cells can recognise and respond to Mtb or Mtb-infected macrophages, and to investigate if γδ T cells can promote phagocytosis and killing of Mtb by macrophages. We expect to identify subsets of γδ T cells that become activated by Mtb-infected macrophages, but not uninfected macrophages. We will then find out if γδ T cells can ‘help’ macrophages kill Mtb. This research may help to identify subsets of γδ T cells that can be targeted for the treatment of tuberculosis. This shows promising advances towards a cure for TB which is both medically effective and economically efficient. γδ T cells can be multipliedin a ‘one donation fits all’ model without the graph vs host disease as a result of their receptor pattern. While this project is only a step towards the aspiring eradication of TB, as we have seen in cancer immunotherapy, cellular immunotherapy for TB could have unprecedented positive results.