Tregonomics Navigating regulatory T cell heterogeneity for adoptive cell therapy

Regulatory T (Treg) cells are specialized CD4⁺ T cells that maintain immune tolerance by suppressing excessive immune responses. Their unique immunosuppressive capacity has made them promising candidates for adoptive cell therapy (ACT) in autoimmune diseases and transplantation. However, current therapeutic approaches are limited by the considerable heterogeneity of the Treg cell compartment and by challenges in isolating pure, lineage-stable Treg cell populations.
This thesis investigates the heterogeneity of human Treg cells across development, differentiation, and therapeutic application. Using single-cell transcriptomics, flow cytometry, and functional assays, we show that Treg cell heterogeneity is already evident during thymic development, identifying distinct developmental and recirculating Treg cell populations within the human thymus. We further demonstrate that in the circulation, the cell surface molecule glycoprotein A33 (GPA33) marks quiescent T cell states in both conventional and regulatory CD4⁺ T cells. Within the Treg cell compartment, GPA33 identifies a previously unrecognized central memory-like Treg cell population characterized by stable lineage commitment, proliferative capacity, and the ability to differentiate into more effector-like Treg cell states. Finally, these biological insights were translated into a practical strategy for Treg cell isolation. GPA33-based selection, particularly in combination with CD226, substantially improves the enrichment of lineage-stable Treg cells and outperforms current isolation strategies based on CD127 and CD45RA expression.
Together, this work provides new insights into human Treg cell heterogeneity and establishes GPA33 as both a marker of Treg cell identity and stability and a promising tool for improving Treg-based immunotherapies.