ST2 enforces a ‘repair-ready’ Treg phenotype that homes to and ameliorates neuroinflammation 2260164

Abstract

Abstract Introduction Regulatory T cell (Treg) therapy faces clinical challenges related to a lack of persistence, stability, homing and scalability. Improvements often address singular issues and fail to engender ‘repair-ready’ cells. Methods We developed GNTI-823, an engineering strategy to generate Tregs (EngTreg) from human CD4 T cells that constitutively express FOXP3 for stability and scalability; contain a rapamycin-activated chemically induced IL-2 signaling complex (CISC) for persistence; and express the IL-33-responsive alarmin receptor ST2 for inflammatory-homing and in vivo functionality. Results ST2 expression successfully conferred a ‘Tissue’ Treg phenotype, characterized by high expression of inflammatory homing receptors, metabolic genes and tolerogenic factors absent from non-ST2 EngTregs or circulating Tregs. Indeed, in a model of ischemic stroke, ST2-EngTreg cells demonstrated preferential homing and improved sensorimotor, learning and memory outcomes. in vitro, ST2-EngTregs sequestered higher amounts per cell of inflammatory factors, IL-33, TNF and IL2 that limit macrophage/microglial and T cell activation. Lastly, ST2-EngTregs remained stable and persisted under prolonged inflammatory and IL-2 scarce conditions. Conclusion Thus, GNTI-823 EngTregs are designed to home, function and persist in neuroinflammatory sites, which show pre-clinical promise for the treatment of ischemic stroke and other neuroinflammatory and degenerative conditions. Funding Source NIH SBIR Topic Categories Translational and Interventional Immunology (TI)