CD70 expression determines the therapeutic efficacy of expanded human regulatory T cells

• Published in: Communications biology Vol. 3; no. 1; p. 375
• Main Authors: Arroyo Hornero, Rebeca, Georgiadis, Christos, Hua, Peng, Trzupek, Dominik, He, Li-Zhen, Qasim, Waseem, Todd, John A, Ferreira, Ricardo C, Wood, Kathryn J, Issa, Fadi, Hester, Joanna
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 14.07.2020; Nature Publishing Group UK
• Subjects: Allergies; Animals; Autoimmunity; Biology; CD27 antigen; CD27 Ligand - genetics; CD27 Ligand - metabolism; CD70 antigen; Clonal deletion; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Female; Flow Cytometry; Forkhead Transcription Factors - metabolism; Gene Editing; Gene Knockout Techniques; Homeostasis; Humans; Immunoregulation; Immunostimulation; Lymphocytes; Lymphocytes T; Mice, Inbred BALB C; Peripheral blood; Phenotypes; Ribonucleic acid; RNA; Sequence Analysis, RNA; T cell receptors; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; T-Lymphocytes, Regulatory - transplantation; Transcriptome; Tumor Necrosis Factor Receptor Superfamily, Member 7 - metabolism
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-020-1097-8

Regulatory T cells (Tregs) are critical mediators of immune homeostasis. The co-stimulatory molecule CD27 is a marker of highly suppressive Tregs, although the role of the CD27-CD70 receptor-ligand interaction in Tregs is not clear. Here we show that after prolonged in vitro stimulation, a significant proportion of human Tregs gain stable CD70 expression while losing CD27. The expression of CD70 in expanded Tregs is associated with a profound loss of regulatory function and an unusual ability to provide CD70-directed co-stimulation to TCR-activated conventional T cells. Genetic deletion of CD70 or its blockade prevents Tregs from delivering this co-stimulatory signal, thus maintaining their regulatory activity. High resolution targeted single-cell RNA sequencing of human peripheral blood confirms the presence of CD27 CD70 Treg cells. These findings have important implications for Treg-based clinical studies where cells are expanded over extended periods in order to achieve sufficient treatment doses.