The role of lung tissue-resident memory T cells in protection against tuberculosis

Tuberculosis (TB) is a global health problem, which is proving extremely difficult to control in the absence of an effective vaccine. Bacille Calmette-Guérin (BCG), the only vaccine currently licensed against TB, demonstrates variable efficacy in humans and cattle. A greater understanding of what constitutes a protective host immune response is required in order to aid the development of improved vaccines. Tissue-resident memory T cells (TRM) are a recently-identified subset of T cells, which may represent an important aspect of protective immunity to TB. This thesis aims to characterise the role of lung TRM in BCG-induced protection against TB. In a mouse model, intravascular staining allowed discrimination between lung-vascular and lung-parenchymal T cells. Experiments demonstrated that BCG vaccination induced a population of antigen-specific lung-parenchymal CD4+ T cells, a putative tissue-resident population. This lung-parenchymal population was significantly increased in frequency following mucosal BCG vaccination, compared to systemic BCG vaccination. This correlated with enhanced protection against Mycobacterium tuberculosis (M.tb) infection in the lungs of mice receiving mucosal BCG, compared to those receiving systemic BCG. Mucosal BCG induced lung-parenchymal CD4+ T cells with enhanced proliferative capacity and a PD1+KLRG1- cell-surface phenotype, a memory-like phenotype associated with improved protection against M.tb infection. These cells may represent a BCG-induced lung TRM population responsible for the enhanced protection observed following mucosal BCG. Overall, this thesis highlights the potential of mucosal vaccination to elicit lung TRM and identifies this as a possible immunological mechanism underlying enhanced protection against M.tb infection. These cells may constitute an important target for future vaccination strategies.