Sentinel Tregs Reinforce Immune Surveillance in the CNS

Regulatory T cells (Tregs) develop in the thymus through agonistic selection, a process driven by recognition of self-antigens. While Tregs are primarily known for their immune-suppressive functions, recent findings suggest that they represent a diverse and multifunctional population. However, whether this diversity extends to tissue-specific immune surveillance remains unclear. Here, we identify and characterize a unique subset of Foxp3+T cells, generated in the thymus and marked by the expression of the opioid precursor gene, preproenkephalin (Penk). Penk+Foxp3+T cells, unlike conventional Tregs, assume an immune-enhancing role in the central nervous system (CNS). During neuronal inflammatory reactions, these cells accumulate in the CNS and secrete synenkephalin (SYEN), a non-opioid peptide derived from Penk. We found that SYEN binds to nicastrin on microglia and macrophages, triggering their activation and amplifying immune responses. In the context of brain cancer, Penk+Foxp3+T cells augment anti-cancer immunity, functioning as sentinel Tregs, that mediate CNS immune surveillance through the SYEN-nicastrin axis. Our findings may provide novel therapeutic opportunities for targeting neuroinflammatory disorders and brain malignancies.