Spatiotemporal control of cytoskeletal remodeling in lymphocytes

T cells use small and dynamic microvilli to efficiently scan cells for abnormalities.

Recognition induces synapse formation; a large polarised interface that drives effector functions e.g. cytotoxic granule release. The importance of the actin cytoskeleton in microvilli and synapse formation is well established.

However, it remains unclear how actin remodeling is spatiotemporally coordinated to drive these structures and whether they are impacted by metabolic state.

This proposal aims to (1) identify the drivers of microvilli formation and dynamics, (2) explain how the cytoskeleton is coordinated from microvillar scanning to synapse formation, and (3) explore the link between cytoskeletal remodeling and metabolism. Aims 1 and 2 will focus on Rho GTPases; the ‘master regulators’ of the actin cytoskeleton.

I will use biosensors, optogenetic manipulators, light-sheet microscopy, and computer vision analyses to quantify and manipulate GTPase signaling networks in relation to microvilli and synapse formation in 4D.

Aim 3 will use biosensors, pharmacological manipulation, and metabolic readouts to examine the impact of metabolic state on microvillar scanning and synapse formation. All aims will use tuneable reconstituted systems to capture and manipulate these key behaviours.

Complete understanding of cytoskeletal remodeling may uncover novel ways to control T-cell function for therapeutic benefit.