Recognition of butyrophilin-family members by gamma-delta T cells
Butyrophilins are a family of stimulatory molecules capable of modulating immune activity. While one type of butyrophilin (3A1) can activate human Vd2+ gamma-delta T cells in the presence of microbial derived phosphoantigen, the molecular mechanism by which this recognition takes place is unclear. Furthermore, there is growing evidence that several different types of butyrophilin and butyrophilin like molecules can be recognised by mouse and human gamma-delta T cells. Hence, we propose to experiment with different combinations of butyrophilin derivates and gamma-delta T cell lines to define which receptor type, binding affinity, and co-stimulatory molecules intervene in the activation of these cells. In the final year of the project in the Kurts laboratory, Germany, the influence of butyrophilin-reactive gamma-delta T cells on dendritic cell activation and cross priming will be examined. These results are of vital importance to better understand the potential of gamma-delta T cells in prospective medical applications.
Improving cross-presentation and vaccination by harnessing MAIT cells
Cross-priming is important for inducing cytotoxic CD8+ T cell responses against intracellular pathogens and tumours. In a collaborative effort between the Kurts and Godfrey laboratories, we recently showed that NKT cell and T helper cell-induced licensing of dendritic cells (DCs) endowed the DC with the capacity to produce distinct chemokines that attract naïve CD8+ T cells towards the cross-priming DCs. This work extends the classical paradigm of T cell activation by Bretscher and Cohn by referring to chemokines as “signal 0”, which acts on T cells before signal 1 (antigen) and signal 2 (costimulation). Like NKT cells, mucosa-associated invariant T (MAIT) cells are an abundant subset of invariant lymphocytes affecting various immune responses against pathogens. MAIT cells recognise bacterially metabolised agents presented by the MR1 molecule on antigen presenting cells. In this project, we propose combining Christian Kurts’ expertise on cross-priming with that of Dale Godfrey on invariant lymphocytes to study whether MAIT cells can license DC for cross-priming against subcutaneous and mucosal pathogens and to resolve how this affects the ensuing immune response. We will clarify how MAIT cells change the cell biological mechanisms by which DC handle antigen for cross-presentation, how they transcriptionally affect DCs, which chemokines are involved and how they affect the migration and interaction of the immune cells involved. Finally, we will test whether MAIT cells can be harnessed to improve vaccination against a mucosal virus infection.