In her PhD work, Anna Vyborova (UMC Utrecht) explored the biology of Vγ9Vδ2T cells, focusing in particular on the biological rationale for Vγ9Vδ2TCR diversity in the interaction with the nonpolymorphic BTN2A1 and BTN3A1 ligands. Key findings include discovery of the spectrum of binding affinities within the diverse Vγ9Vδ2TCR repertoire, and the development of bispecific Vγ9Vδ2TCR-based molecules (GABs) to redirect αβT-cells. Her work also highlights the functional diversity of γ9δ2T cells in immunotherapy.
γδT cells occupy a unique position between the innate and adaptive immune system. They bridge the gap between αβT cells, which monitor for ‘non-self’ signals, and NK cells, which act when ‘self’ is absent. What sets γδT cells apart is their ability to quickly respond to cellular stress—what is known as the ‘altered self.’ This makes γδT cells attractive candidates for immunotherapy, particularly in tumors with low mutational burdens where traditional αβT cell therapies struggle. The PhD thesis by Anna Vyborova, MD (Center for translational Immunology, UMC Utrecht) focused on γδT cell biology, specifically the Vγ9Vδ2T cell receptor (TCR), a key player in recognizing phosphoantigens, organic molecules that accumulate in certain infections and malignant cells. Though the Vγ9Vδ2TCR’s unique reactivity to these molecules was discovered in the 1980s, the mechanisms through which intracellular signals are presented at the cell membrane and how the receptor interacts with its ligand remained long unclear.
Anna Vyborova, MD PhD
The first part of Anna Vyborova’s thesis investigates the interaction between the Vγ9Vδ2TCR and its ligand, building on earlier discoveries about butyrophilin (BTN) family proteins. Vyborova analyzed the diversity of the Vγ9Vδ2TCR’s CDR3 regions and showed that this variations underlie a spectrum of binding affinities for the composite Vγ9Vδ2TCR ligand. The team also developed a novel therapeutic strategy: γδTCR Anti-CD3 bispecific molecules (GABs), which activate αβT cells and demonstrate promise against cancers sensitive to γδT-cell recognition. Higher-affinity Vγ9Vδ2TCRs—whether expressed in genetically engineered αβT cells (TEGs) or incorporated into bispecific constructs—were more effective at targeting tumors. In addition, the research identified RhoB as essential for sensitizing target cells to γδT cell responses, offering a potential biomarker for selecting patients suited to Vγ9Vδ2TCR–based therapies.
In part two of her thesis, Vyborova studied how the diversity of the Vγ9Vδ2TCR repertoire relates to T cell phenotype, focusing on the CDR3δ region. The findings suggest that high-affinity TCRs have a growth advantage in phenotypically ‘young’ cells, particularly in early childhood. Expression of certain NK receptors correlates with high-affinity TCRs, which could aid in identifying optimal subsets for clinical use.
Vyborova examined the transcriptional and functional heterogeneity of γ9δ2T cells, crucial for selecting optimal effectors in the adoptive cell therapy setting. The research identified two subsets—type 1- and type 2-skewed effectors—each with distinct functional, phenotypic and transcriptional profiles. Type 1 γ9δ2T cells, with a strong interferon-γ response and high proliferation, are ideal effectors for immunotherapy. Type 2 cells, producing interleukins IL-4 and IL-5, may play a critical role in sustaining the immune response.
Vyborova concludes: “My thesis provides a deeper insight in the complex biology of human γ9δ2T cells and the Vγ9Vδ2TCR as key to their functional diversity. These findings enhance our fundamental understanding and open the door to new therapeutic strategies in cancer immunotherapy.”
Anna Vyborova, MD (1988, Minsk, Belarus) defended her PhD thesis on September 9, 2025 at Utrecht University. The title of the thesis was “Better begins with different – Navigating the diversity of the γ9δ2T cell receptors, phenotypes and functions”. Supervisor was prof. Jürgen Kuball, MD PhD (Department of Hematology and Center for Translational Immunology, UMC Utrecht). Co-supervisor was Zsolt Sebestyén, PhD (Center for Translational Immunology, UMC Utrecht). Anna works as a hematology resident at UMC Utrecht.
