Clonal and functional T cell determinants of protection and pathogenesis in tuberculosis. (360G-Wellcome-306550_Z_23_Z)

Tuberculosis (TB), resulting from infection with Mycobacterium tuberculosis (Mtb), kills 1.5 million people per year. The immune system prevents disease in most people who become infected, but the mechanisms of immune protection and pathogenesis remain critical knowledge gaps. T cells are necessary for protective immunity, but we do not know the precise T cell traits that influence different outcomes of infection. People living with HIV (PLWH) have persistently increased TB disease-risk and exhibit persistent abnormalities of T cell clonal and functional repertoires, despite long-term antiretroviral therapy (ART). We will use cutting-edge methodology to comprehensively detail perturbation of in vivo human Mtb-reactive T cell responses in this group, independent of total T cell counts. We will test the hypothesis that dominant Mtb-reactive T cells in ART-treated PLWH have restricted clonality, target different antigens and exhibit different functionality, compared to those of HIV-negative individuals. We will identify which of these T cell traits impact on macrophage control of Mtb-growth, and predict disease-risk in multiple independent cohorts sampled from the general population. We expect our findings to drive innovations in vaccine development and evaluation, personalised risk-stratification to enable precision targeting of preventative antimicrobial treatment, and development of immunomodulatory therapies for disease.