The adaptive immune system has evolved to specifically recognize and destroy a virtually infinite variety of pathogens, while remaining unresponsive towards self-tissues, a state known as immune tolerance. T cell-based antigen-specific immune tolerance was first postulated in 1970. Yet, it was not until the 1990s that the identity of the cell type responsible for this phenomenon was firmly established: regulatory T cells (Tregs).

Manipulating human Tregs offers the unprecedented opportunity to induce tolerance in a clinical setting, potentially providing cures for autoimmune disease and transplant rejection. However, vanishingly low numbers of antigen-specific Tregs and Treg instability upon prolonged expansion have hampered the implementation of Treg-based therapies.

Chimeric antigen receptor (CAR) technology has greatly expedited the generation of tumor antigen-specific effector T (Teff) cells. CARs are synthetic receptors comprising an extracellular antigen-binding domain and an intracellular signaling domain that allow for potent T cell activation directly downstream of antigen recognition.

Adoption of the CAR platform for Treg engineering represents a promising strategy to generate custom-made antigen-specific Tregs for therapy. Yet, there are marked differences in signaling and function between Tregs and Teff cells. My goal is to design the next generation of CARs for Treg therapy, aiming to establish tolerance in the contexts of autoimmune disease and transplant rejection.