Activation and switch of fates in T lymphocytes.

Introduction

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.

Project Goal

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.

Methodology

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 to:

• Characterize an unprecedented transient stage of activated T cells.
• Determine the early gene expression signatures and fate choices of in vivo activated naïve and memory T cells.
• 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.

Future Directions

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.

Conclusion

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.