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T cells: Regulation of Original diversity And Diversification after activation (T cell ROAD)

Objective

T cell diversification during immune responses to infections or vaccines is key for combating an infection and the concomitant establishment of immune memory. This diversification is established phenotypically, functionally, transcriptionally and epigenetically. The ability of a cell to generate progeny with diverse fates is a general feature of stem cells and, as such, naïve as well as memory T cells have stem cell characteristics. At the core of this proposal is the key question of how - mechanistically - a naïve or memory mouse or human T cell generates progeny with different fates. We will address this key question from two complementary but also interconnected angles: First, we will investigate the role of established heterogeneity within the pool of naive CD8 T cells before activation. We recently uncovered cellular morphology coupled to distinct TCR signalling strength as a novel aspect of heterogeneity within naïve human and mouse T cells and could link this phenotype to differential fate adoption of their progeny after activation. We will now investigate this novel aspect of naïve T cell heterogeneity to unravel the mechanisms that instil and maintain these morphological differences in naïve T cells and how these differences confer altered TCR stimulation responsiveness. Second, we will study the mechanisms employed by CD8 T cells to generate diversity in response to antigen recognition and how these are interconnected to preceding naïve T cell heterogeneity. We will specifically interrogate the role and mechanism of asymmetric cell division (ACD) in T cell fate diversification upon TCR-mediated activation. These anticipated novel insights into T cell diversification mechanisms will not only deepen our knowledge of a fundamental biological process but will enable us to guide naive T cells in a tailored manner along their “T cell ROAD” - to improve T cell-based immunotherapeutic modalities for longer-lasting effects.

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Keywords

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Programme(s)

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Topic(s)

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HORIZON-ERC - HORIZON ERC Grants

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Call for proposal

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(opens in new window) ERC-2025-ADG

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Host institution

EIDGENOESSISCHE TECHNISCHE HOCHSCHULE ZUERICH
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 2 500 000,00
Address
Raemistrasse 101
8092 Zuerich
Switzerland

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Region
Schweiz/Suisse/Svizzera Zürich Zürich
Activity type
Higher or Secondary Education Establishments
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Total cost

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No data

Beneficiaries (1)