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SUMMARY:Optical control of T-cell signalling dynamics - Dr John James\; De
 partment of Medicine\, University of Cambridge
DTSTART:20180322T130000Z
DTEND:20180322T140000Z
UID:TALK101059@talks.cam.ac.uk
CONTACT:Bobbie Claxton
DESCRIPTION:We have a near-complete characterisation of the components for
  many biological signalling networks\, but their dynamic interconnections 
 remain poorly understood. Current methods to investigate intracellular sig
 nalling generally disrupt one point in the network and compare cell functi
 on afterwards. However\, the intervention can never be made without pertur
 bing the rest of the system and rarely provides the dynamic information re
 quired for a mechanistic understanding of network function. We investigate
  cell signalling by providing quantitative and dynamic inputs to the intac
 t network\, measure the corresponding functional outputs and then infer ch
 aracteristics of the underlying system. To achieve the required spatio-tem
 poral control over signalling\, we have developed light-controlled biologi
 cal components that enable us to modulate both the intensity and frequency
  of signalling within the network. We currently focus on the intracellular
  signalling of T-cells\, an essential immune cell-type that detect infecte
 d cells and orchestrate their removal. \nI will discuss two projects from 
 my lab in the talk. The first part is on LCK\, a tyrosine kinase that is e
 ssential for initiating T-cell antigen receptor (TCR) signalling. We have 
 used genetic code expansion to engineer a photocaged version of LCK that c
 an be switched ‘on’ through brief light stimulation. Using this approa
 ch\, we have found that in live cells\, autophosphorylation of the LCK act
 ive-site loop is indispensable for its catalytic activity. We have leverag
 ed the power of this approach to show that CD4 and CD8\, the T-cell corece
 ptors\, can enhance LCK activity\, thereby helping to explain their effect
  in physiological TCR signalling. \nFor the second project\, we have engin
 eered an optically-controlled chimeric antigen receptor (OptoCAR) that pro
 vides a means to rapidly and reversibly manipulate the flux through the TC
 R signalling pathway. We have used this exciting new tool to directly inve
 stigate whether the downstream signalling network has the capacity to inte
 grate or ‘remember’ previous antigen-presenting cell encounters\, and 
 the timescales over which this could occur. \nUsing our new tools\, our ke
 y goal is to provide a quantitative understanding of how different T-cell 
 inputs are decoded by the dynamics of the signalling pathways to specify t
 he appropriate response. Through this\, we hope to discover parts of the n
 etwork that could be fine-tuned therapeutically to alleviate diseases when
  T-cell function becomes deleterious.
LOCATION:Babraham - The Cambridge Building\; Kings Hedges Room
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