ReSpecTreg · Resolve human autoantigen-specific regulatory T cell responses

Antigen-specificity is the key feature of adaptive immunity, orchestrated by CD4 T helper (Th) cells. A small CD4+ subset of autoreactive Foxp3+ regulatory T cells (Tregs) secures tolerance against self and contributes to tissue homeostasis and regeneration. It is a central question in immunology how Tregs exert these various functions. In humans, however, self-specific Treg and Th cells are challenging to track and thus remain poorly characterized. In particular, the specific autoantigens targeted by Tregs remain elusive. Consequently, essential information about human self-specific Tregs' generation, function, and therapeutic potential is missing. This fundamental knowledge gap limits our understanding of human immune tolerance mechanisms and prevents their therapeutic application. We have developed sensitive cytometric technologies for deep molecular and functional characterization of human autoantigen-specific Th cells in various chronic autoimmune diseases (AIDs), identifying a novel Foxp3+ Th cell subset induced by chronic antigen stimulation. Furthermore, screening Treg responses against a wide range of self-antigens in healthy donors revealed Treg responses against known AID target antigens and against novel antigens potentially involved in tissue homeostasis or regeneration.Based on this prior work, RespecTreg will build a unique map of human Treg self-reactivity and deeply characterize prototypic Treg and Th cell responses: RespecTreg will explore fundamental mechanisms of Treg functions and their failure, identify relevant Treg target antigens, analyze Treg antigen receptor (TCR) characteristics, define antigen-related Treg functional diversity, and elucidate mechanisms of their induction and persistence. We will precisely characterize disease-relevant T cell responses in human AIDs or tissue damage. This will guide tailor-made antigen-specific Treg generation for future Treg-based therapies.