Mechanisms regulating the shutdown of cytotoxic T cell populations in acute and persistent viral infections

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Apoptosis, or programmed cell death, is the form of cell death responsible for removal of unwanted or excess cells from the body. This is an essential mechanism to allow remodelling of tissues as an embryo grows and is a crucial way in which the body prevents the unwanted outgrowth of individual cell types. Control of cell growth in this way is a key checkpoint in preventing cancers. This regulatory mechanism is also important in determining the number and type of immune cells that are generated at steady state and following an immune response. Two families of proteins are essential in initiating this process of apoptosis. One is known as the BH-3-only family, while the other is the tumour-necrosis receptor (TNFR) family. These families are made up of several family members, each of which responds to different types of stimuli, and are expressed in different tissues in the body. So far only one BH-3-only family member, BIM, has been identified to regulate shut-down of an immune response. This action prevents the generation of large numbers of highly aggressive cells that are specific for a pathogen inadvertently causing damage to the body. This control checkpoint is a normal, but vital, part of the immune response. Other members of these families are also likely to play an important role in this process, but as yet their identity is unknown. This study will determine which members of the BH-3-only and TNFR family members play a role in (i) regulating the numbers of lymphocytes present at steady state, and (ii) in the shut-down process in different types of pathogen infection. This work will provide insight into how lymphocytes are regulated in the resting animal, and in disease.