Potent Bidirectional Cross-Talk Between Plasmacytoid Dendritic Cells and γδT Cells Through BTN3A, Type I/II IFNs and Immune Checkpoints

Plasmacytoid DCs (pDCs) and gamma delta T cells are both critical players in immunosurveillance against pathogens and cancer due to their ability to sense microbes and cell stress through recognition of pathogen-associated molecular patterns or altered metabolism [phosphoantigens (PAgs)]. Their unique features, high functional plasticity and ability to interact with many immune cell types allow them to bridge innate and adaptive immunity, initiating and orientating widely immune responses, hence contributing to protective and pathogenic immune responses. Yet, despite strategic and closed missions, potential interactions between pDCs and gamma delta T cells are still unknown. Here we investigated whether there is interplay between pDCs and gamma delta T cells and the underlying molecular mechanisms. Purified human pDCs and gamma delta T cells were cocultured in presence of TLR-L, PAg, and zoledronate (Zol) to mimic both infectious and tumor settings. We demonstrated that TLR7/9L- or Zol-stimulated pDCs drive potent gamma delta T-cell activation, Th1 cytokine secretion and cytotoxic activity. Conversely PAg-activated gamma delta T cells trigger pDC phenotypic changes and functional activities. We provided evidence that pDCs and gamma delta T cells cross-regulate each other through soluble factors and cell-cell contacts, especially type I/II IFNs and BTN3A. Such interplay could be modulated by blocking selective immune checkpoints. Our study highlighted crucial bidirectional interactions between these key potent immune players. The exploitation of pDC-gamma delta T cells interplay represents a promising opportunity to design novel immunotherapeutic strategies and restore appropriate immune responses in cancers, infections and autoimmune diseases.