Tuberculosis (TB) is a leading cause of death worldwide. Mycobacterium tuberculosis (Mtb) is increasingly resistant to antibiotics and is a global threat to public health. Therefore, there is an urgent need to develop host-directed therapies (HDT). Innate immunity plays an essential role in mediating the early response to Mtb infection, and can result in eradication of the bacteria. However, Mtb can subvert innate immune responses, allowing bacterial replication inside macrophages. Emerging evidence indicates that innate cells such as monocytes/macrophages can be “trained” to enhance their response to pathogens. However, the effect of innate immune training on the induction of human adaptive immune responses remains unknown. Adaptive Th1 and Th17 cells have been shown to play both protective and pathological roles in TB disease. In settings of inflammation, Th17 cells can be plastic, switching into “ex-Th17” cells that produce IFN-γ, similar to Th1 cells. I have reported that ex-Th17 cells accumulate in the joints of patients with rheumatoid arthritis, exhibiting a long-lived stem-cell like phenotype and are highly resistant to suppression by Treg cells. Furthermore, ex-Th17 cells exacerbate inflammation by activating surrounding synovial fibroblasts. In the lungs of patients with sarcoidosis, an autoimmune disease which shares many clinical features of TB, ex-Th17 cells are the major source of pathological IFN-γ rather than Th1 cells. My preliminary data shows that the CD4 response to Mtb is mediated by a heterologous population of bona fide Th1 and ex-Th17 cells. Furthermore, manipulating macrophage function can modulate ex-Th17 responses. This research will define the role of innate immune training in the induction of T cell responses in TB patients. It will analyse the protective versus potentially pathogenic roles of Th1 and plastic Th17-lineage cells in TB. These findings may inform the design of innovative drugs and vaccine strategies with the potential to revolutionise TB healthcare.
