CRISPR screening in primary human CD8 T cells identifies regulators modulating CD8 TEMRA differentiation

CD8 T cells are the essential adaptive immune cell types performing cytotoxic functions in our body, that play a decisive role in fighting against many types of non-communicable diseases and infectious diseases. During the ageing process, the end-stage CD8 T cell subset, namely, terminally-differentiated effector memory CD8 T cells (CD8 TEMRA) accumulate and gradually dominate the CD8 T-cell memory compartment in the elderly. This type of cells, although with reduced proliferative capacity and several other features similar to that of senescent cells, still possess high potential to perform multiple effector functions, such as secretion of several pro-inflammatory cytokines and execution of cytotoxic functions.
We and others have recently shown that CD8 TEMRA are evidently dysregulated in various human diseases, including Parkinson’s disease (PD) and Alzheimer’s diseases. Notably, in contrast to many other types of memory and naïve subsetsof CD8 T cells, CD8 TEMRA only exist in humans, but not in the widely-used animal models, i.e., mice. As a consequence,
there still exists a huge knowledge gap in many fundamental aspects, such as detailed molecular mechanisms underlying development/differentiation and functional consequence regarding CD8 TEMRA. This project aims to advance knowledge development in comprehending differentiation mechanisms, i.e., by systematically identifying regulators promoting or inhibiting the differentiation process towards CD8 TEMRA using large-scale CRISPR screening in primary human CD8 T cells. A focus will be put on the discovery of the regulatory mechanisms modulating skewed CD8 TEMRA differentiation in PD, especially the potent ‘rescuing’ regulators.