Activation and switch of fates in T lymphocytes. (ActSwiftly)

Antigen-stimulated naïve CD8+ T cells proliferate and differentiate into effector and memory cells. Whereas effector T cells remove infected or cancerous cells, memory T cells protect the organism from re-infections.

Despite decades of research, the challenging central questions of how naïve T cells form diverse progeny and what drives the differential response of naïve and memory T cells to infection remain unanswered, largely because of lacking experimental tools.

The goal of this project is to generate a comprehensive model of cell-fate choices of naïve and memory CD8+ T cells in vivo.

We will achieve this by addressing three complementary specific objectives: 1) To understand the early and late fate choices in naïve T cells. 2) To uncover differences between naïve and memory T-cell responses and fates. 3) To identify the role of proximal protein kinases LCK and FYN in T-cell fate choices.

We will pursue these aims using a combination of experimental immunology and systems biology.

We used the synergy between novel genetic models and single cell atlases (i) to characterize an unprecedented transient stage of activated T cells, (ii) to determine the early gene expression signatures and fate choices of in vivo activated naïve and memory T cells, and (iii) to observe that LCK secures memory T-cell formation.

These tools and findings offer us novel perspectives to tackle the challenging objective in its full complexity.

We will develop additional unique experimental models coupled with innovative in-silico techniques to uncover the cellular and molecular mechanisms underlying diverse fate choices of particular T-cell subsets and to narrow the gap between mouse and human immunology.

Overall, this project has the ambition to resolve long-standing fundamental questions in immunology to open new avenues for targeting and modulating T-cell fates in vivo for efficient vaccine design and for promoting beneficial cytotoxic responses to chronic infections and cancer.