Background I aim to research the interaction between human immune cells (T-cells) and a specific protein (CD1c) which may play a key role when fighting tuberculosis (TB) infection. The knowledge created by this research project will help to direct future, more successful treatments for TB. TB is a lung infection that spreads by people coughing. It continues to cause disease worldwide, killing over 4,000 people every day, and is becoming progressively more resistant to the antibiotics used to treat it. New approaches to control the disease are urgently needed as standard vaccination, diagnosis and treatment have remained largely unchanged for over 40 years. A human protein called CD1c binds fatty substances on the cell surface in order for human immune cells (called T-cells) to recognise them, these T cells can then protect us from infection. CD1c can also bind substances from the bacteria that causes TB and then show them to T-cells to activate them. However, many T-cells that recognise CD1c bound to bacterial components (such as TB) also seem to recognise CD1c bound to fatty substances derived from our own cells. Currently, it is not understood how these T-cells that exhibit dual recognition of our own cells and bacteria, work within the context of human tuberculosis infection. I propose that CD1c and its T-cells regulate the interface between the TB causing bacteria and its human host and will investigate this using a range of cutting edge scientific approaches. Aims To fully understand CD1c and the role of responsive T-cells in human TB infection, I will proceed from understanding the fundamental process of how cells communicate through the binding of CD1c to its receptor and then move to studies in patients and infected cells. I will perform detailed studies at the molecular level to understand how CD1c binds and presents fatty lipid components to T-cell receptors through a combination of techniques including structural, mutational, computational, and cellular methods that will help to dissect the fundamental basis for binding of T-cells to CD1c. I will then investigate how CD1c responsive T-cells recognise fatty lipid components that are shared by human and bacterial cell walls. For this I will isolate T-cells from human blood and tissues, and investigate their reactivity to fatty components that are shared by human and bacterial cells. Finally, I will investigate the role of CD1c and its T-cells in human TB infection through employing a newly developed TB infection cell culture model using tiny 3 dimensional spheres within which human cells are infected with TB bacteria. This model is a closer representation of what happens in TB infected human lung. I will investigate the role of CD1c by modulating its expression and through manipulating the pathways that control the levels of fatty components that are produced in cells. I will also augment the infected spheres with CD1c-responsive T-cells in order to fully understand their functional impact in human TB infection. Application benefits This study will perform the first in depth investigation of the role of CD1c and its T-cells in human TB. My findings will result in new discoveries that could deliver new treatment opportunities to help tackle the TB pandemic and the basic scientific findings will also be relevant to treating cancer and inflammatory disease. This will help to keep the UK at the forefront of the research area and more importantly will help the many people affected by TB worldwide.