What We Know
Whereas adaptive lymphocytes become activated by recognizing foreign antigens, a major strategy of innate lymphocyte activation is via the recognition of self ligands that are constitutively present and may also become altered during times of stress or “danger”). The innate T lymphocyte populations we study – iNKT cells, Vγ9Vδ2 T cells, and MAIT cells – all respond to lipid-related cues. This focus on the status of the “lipidome”, probably allows these cells to sensitively monitor the overall physiological state, since the lipidome will rapidly become perturbed during periods of rapid cell growth as well as during inflammatory events.
Our Overarching Questions
We are interested in answering questions such as:
- What are the endogenous pathways that control the activation of innate T lymphocytes (i.e. how are innate T lymphocytes activated in ways that do not require microbial infection, and are these pathways different in the context of cancer, immune reconstitution, or immunological homeostasis)?
- How do iNKT cells interact with dendritic cells to drive the activation of other lymphocytes (e.g. T cells and NK cells) to fight cancer?
- How do iNKT cells interact with monocytes to silence T cell responses (i.e. how do iNKT cells prevent graft-versus-host disease or other forms of immunopathology)?
- What signals cause γδ T cells and MAIT cells to directly target cancer cells for killing?
How We Will Get There
To address these questions, we have developed a number of novel human-immune-system mouse models. These model systems have allowed us to build on information gained from in vitro and ex vivo studies of human innate T lymphocytes, and to address the effects of our human innate T cell-based immunotherapies in vivo.