Temporal genetic switches define the constraints of finite Treg repertoires 9018

Abstract Description Foxp3-expressing CD4 regulatory T cells possess a diverse T-cell receptor repertoire and are pivotal in suppressing autoimmune responses, conferring tolerance to innocuous foreign antigens, such as food and commensal microbiota, and maintaining tissue integrity. The Treg repertoire is presumably continuously shaped by newly induced Treg cells and the turnover of old Treg cells. However, the temporal and spatial dynamics, as well as their immunological function, of the Treg repertoire remain to be fully elucidated. Here, we employ parabiosis to demonstrate that Treg cells undergo continuous circulation in the steady state, implying systemic immune surveillance. Timestamp tracing revealed continuous thymic Treg development and incorporation into the peripheral Treg cell pool, raising a question about their biological roles. By manipulating the Treg determinant with temporal inducible genetic switches, we engineered mice with tunable Treg repertoires. Surprisingly, Treg cells with a finite repertoire are sufficient to effectively control autoimmunity, yet exhibit marked susceptibility to immune perturbations, such as tumor growth. Mechanistically, these Treg cells are constrained in response to immune challenges, suggesting a pivotal role for continuous Treg development. These results collectively elucidate an indispensable characteristic of Treg repertoire, offering valuable insights for understanding Treg-mediated immune regulation and improving therapeutic approaches. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)