Research Projects

Gamma-delta (γδ) T cells are a critically important component of the immune system. They are often enriched in non-lymphoid tissues and respond rapidly to infection by producing inflammatory cytokines, proliferating and acquiring cytotoxicity potential. Unlike alpha-beta (αβ) T cells, which primarily respond to antigenic peptides in the context of MHC, most γδ T cells in humans react to small phosphorylated non-peptide molecules called ‘phosphoantigens’. However, the molecular mechanism underpinning this recognition is a mystery. In the 25 years since the discovery of phosphoantigens, researchers have confirmed that some form of antigen-presenting molecule other than MHC is important, however, the identity of this ligand was a mystery. We have recently discovered that a surface protein called ‘butyrophilin 2A1’ is critical and enables γδ T cells to respond to phosphoantigen (ref #1). We are offering a project to further explore this novel form of antigen presentation, including an examination of how phosphoantigen-binding triggers γδ T cells to become activated, and whether other ligands are involved. Answers to these fundamental questions will hopefully lead to the development of new treatments for cancer, as well as infectious disease.

Image: Human gamma-delta (γδ) T cells become activated in response to microbial and cancer-derived phosphoantigens, and we have discovered that a cell-surface protein called “butyrophilin 2A1” is essential, and that it functions in cooperation with another related molecule called “butyrophilin 3A1”. Together, these molecules bind to the T cell receptor expressed on γδ T cells and initiate an immune response.

Ref #1. Marc Rigau et al. Butyrophilin 2A1 is essential for phosphoantigen reactivity by γδ T cells. Science. 2020 Feb 7;367(6478):eaay5516.

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