Effector memory–type regulatory T cells display phenotypic and functional instability
Désirée J. Wendering, Leila Amini, Stephan Schlickeiser, Martí Farrera-Sal, Sarah Schulenberg, Lena Peter, Marco Mai, Tino Vollmer, Weijie Du, Maik Stein, Frederik Hamm, Alisier Malard, Carla N. Castro, Mingxing Yang, Ramon Ranka, Timo Rückert, Pawel Durek, Frederik Heinrich, Gilles Gasparoni, Abdulrahman Salhab, Jörn Walter, Dimitrios L. Wagner, Mir‐Farzin Mashreghi, Sybille Landwehr-Kenzel, Julia K. Polansky, Petra Reinke, Hans‐Dieter Volk, Michael Schmueck‐Henneresse
Abstract
Regulatory T cells (T reg cells) hold promise for sustainable therapy of immune disorders. Recent advancements in chimeric antigen receptor development and genome editing aim to enhance the specificity and function of T reg cells. However, impurities and functional instability pose challenges for the development of safe gene-edited T reg cell products. Here, we examined different T reg cell subsets regarding their fate, epigenomic stability, transcriptomes, T cell receptor repertoires, and function ex vivo and after manufacturing. Each T reg cell subset displayed distinct features, including lineage stability, epigenomics, surface markers, T cell receptor diversity, and transcriptomics. Earlier-differentiated memory T reg cell populations, including a hitherto unidentified naïve-like memory T reg cell subset, outperformed late-differentiated effector memory–like T reg cells in regulatory function, proliferative capacity, and epigenomic stability. High yields of stable, functional T reg cell products could be achieved by depleting the small effector memory–like T reg cell subset before manufacturing. Considering T reg cell subset composition appears critical to maintain lineage stability in the final cell product.