Deciphering the molecular basis of Vγ9Vδ2 T cell activation
Deciphering the molecular basis of Vγ9Vδ2 T cell activation
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Human Vγ9Vδ2 T cell activation is tightly regulated by Butyrophilin (BTN) proteins expressed on target cells. Human Vγ9Vδ2 T-cell activation relies on the coordinated action of BTN2A1, BTN3A1, BTN3A2, and BTN3A3 in response to phosphoantigen accumulation. Although their essential roles have been firmly established, the molecular principles that govern how these proteins associate with one another, select specific interaction partners, and organise at the cell surface remain poorly understood. Our laboratory employs an extensive collection of mutants and chimeric molecules to uncover the structural and functional determinants that drive these interactions and enable optimal Vγ9Vδ2 T cell activation.
Our research aims to understand:
How BTN proteins interact with the γδ T cell receptor (γδTCR)
How different BTN family members cooperate during T cell activation
How cellular stress and metabolic changes influence these interactions
Which molecular features determine immune recognition and activation strength
Comparative biology of human and alpaca/Camelids
Comparative biology of human and alpaca/Camelids
Why do humans require three BTN3 proteins to activate Vγ9Vδ2 T cells, while alpacas achieve a similar response with just one? The absence of these cells and their associated BTN genes in conventional rodent models has made such questions difficult to address. Our previous work in the laboratory of Prof. Thomas Herrmann identified alpaca as a unique comparative model, possessing human-like phosphoantigen-responsive Vγ9Vδ2 T cells but a much simpler BTN system. By combining evolutionary, structural, and molecular approaches, we use this simplified system to uncover the fundamental principles governing Vγ9Vδ2 T-cell activation.
By combining molecular immunology, cell biology, protein engineering, and functional immune assays, we aim to uncover the detailed mechanisms governing γδ T cell activation. These studies will provide important insights into immune surveillance and may help develop new strategies for cancer immunotherapy and infectious disease research.
Immunomodulatory roles of Butyrophilin proteins
Immunomodulatory roles of Butyrophilin proteins
Butyrophilin (BTN) and BTN-like proteins are increasingly recognised as important regulators of immune responses. Different BTN family members shape immune responses in distinct ways, either promoting or restraining immune activation depending on the biological context.
Many aspects of BTN biology, however, remain poorly understood.
Our laboratory is particularly interested in exploring:
The pro- and anti-tumour functions of BTN proteins
How BTNs shape immune responses within the tumour microenvironment
The role of BTNs during infection and inflammation
Structural and functional features that regulate BTN-mediated signalling
Crosstalk between BTN proteins and other immune regulatory pathways
Understanding these mechanisms may reveal how tumours evade immune responses and how BTN-mediated pathways can be therapeutically targeted to improve immune-based treatments.
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