Charting alternative splicing dynamics and regulation in T-cells

Alternative splicing is a complex process influenced by a multitude of factors enabling cells to produce different protein variants from the same gene, thereby increasing cellular phenotypic diversity.

While it is a highly used mechanism for immune cells to fine-tune and adapt their responses to various challenges, aberrant splice patterns are frequently found in dysfunctional T-cells, potentially compounding their defects.

However, there is a profound lack of understanding about how splicing decisions are regulated during different stages of T-cell development and activation, the heterogeneity of used splice events, underlying signaling networks, and ultimately their functional consequences in T-cells. In this proposal we aim to tackle these questions and advance our understanding of splicing regulation in T-cells.

We will gain a comprehensive, genome-wide understanding of alternative splicing dynamics and regulation through the development of novel multi-modal single-cell technologies and vitro differentiation and stimulation assays of human T-cells.

We will uncover splicing variation and contribution to T-cell response as well as elucidate functional consequences through CRISPR interference screens. Uncovering the molecular mechanisms of splicing has immense clinical implications.

We anticipate that it will be crucial to remedy immune mediated diseases and could lead to more accurate engineering of T-cells, as well as strategies to revert cells out of dysfunctional states.