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Rewriting memory; Manipulation of T cell memory to enhance vaccine efficiency

Project title: Rewriting memory; Manipulation of T cell memory to enhance vaccine efficiency

Fund: Croatian Science foundation, grant IP-06-2016-8027

Duration: 01.07.2017 – 30.06.2021

Coordinator: University of Rijeka, faculty of medicine

Total value of the project: HRK 1.000.000

Brief description:

CD8 T cell mediated immunity protects us against pathogens and cancer. The naïve T cell pool consists of millions of clones, each one unique based on its T cell receptor (TCR). Upon infection, only a few of these clones are recruited to generate antigen-specific memory. Selection of memory clones is a trade-off between specificity and diversity; too much specificity restricts antigen-recognition, which precludes responsiveness against pathogens with small mutations. Too much diversity impairs efficiency of recall responses. Mechanisms controlling memory diversity are largely unknown. Recently, we have identified the transcription factor Eomes as a key mediator of memory formation. Low-intensity stimulation upregulates Eomes and promotes development of T cell memory. High-intensity stimulation downregulates Eomes, and promotes effector cell differentiation. How an activating signal is translated to a certain level of Eomes induction is currently unknown. Also, it is unclear how Eomes mediates memory formation and whether we can target this signaling pathway to enhance immunological memory.

In this project, we will study the impact of activating T cell receptor signal intensity on memory formation via the transcription factor Eomes. First, we will investigate how TCR signal strength impacts the quality and quantity of activation of its main downstream components and how this translates into the activation of Eomes. In parallel, we will investigate how Eomes translates TCR-activating stimuli of a given strength in a molecular process that promotes memory formation. Using the combined information of these two lines of inquiry, we will identify and validate key factors that mediate these processes in the third phase of the project. Importantly, we will select for molecules that can be targeted by pharmacological means. Finally, we will test the potency of therapeutic intervention on the formation of specific memory. We will attempt to enhance the scope of antiviral memory to improve its ability to recognize more viral mutants. In parallel, we aim to reduce the scope of tumor-directed memory cells, to improve their specificity and reduce off-target effects.

Project objectives and expected results:

Overall research question: How is an CD8 T cell activating signal of a given strength translated into the capacity to form memory and can we exploit this mechanism to improve T cell vaccines against viruses and cancer?

Research goals:

  1. To elucidate how T cell receptor signal strength affects proximal signaling and how it leads to Eomes induction.
  2. To find out what the molecular mechanism is via which Eomes shapes CD8 T cell memory.
  3. To identify and characterize potential therapeutic targets for modification of the memory CD8 T cell pool.
  4. To manipulate therapeutic targets to improve vaccines against viruses and tumors.

Relevant Web pages:

https://sites.google.com/view/tcellmemory/home/project-rewriting-memory

https://www.hrzz.hr/default.aspx?id=78&pid=4305&rok=2016-06

Contact person:

Dr. Felix M Wensveen

E-mail: felix.wensveen@medri.uniri.hr

Phone: 00385 51 651 293