Helios is a marker, not a driver, of human Treg stability. Issue 1 (13th October 2021)

• Record Type: Journal Article
• Authors: Lam, Avery J.; Uday, Prakruti; Gillies, Jana K.; Levings, Megan K.
• Is Part Of: European journal of immunology. Volume 52:Issue 1(2022)
• Page Start: 75
• Page End: 84
• Publication Date: 2021-10-13
• Subjects: cell therapy -- Helios -- CRISPR‐Cas9 -- Treg stability -- regulatory T cells; Immunology -- Periodicals; 616.079
• DOI: 10.1002/eji.202149318
• Languages: English
• ISSNs: 0014-2980

Abstract

Abstract: Treg therapy holds promise as a potentially curative approach to establish immune tolerance in transplantation and autoimmune disease. An outstanding question is whether therapeutic Tregs have the potential to transdifferentiate into effector T‐cells and, thus, exacerbate rather than suppress immune responses. In mice, the transcription factor Helios is thought to promote Treg lineage stability in a range of inflammatory contexts. In humans, the role of Helios in Tregs is less clear, in part, due to the inability to enrich and study subsets of Helios‐positive versus Helios‐negative Tregs. Using an in vitro expansion system, we found that loss of high Helios expression and emergence of an intermediate Helios (Helios mid )‐expressing population correlated with Treg destabilization. We used CRISPR/Cas9 to genetically ablate Helios expression in human naive or memory Tregs and found that Helios‐KO and unedited Tregs were equivalent in their suppressive function and stability in inflammation. Thus, high Helios expression is a marker, but not a driver, of human Treg stability in vitro. These data highlight the importance of monitoring Helios expression in therapeutic Treg manufacturing and provide new insight into the biological function of this transcription factor in human T‐cells. Abstract : Tregs that have destabilized during in vitro expansion are associated with intermediate expression of the transcription factor Helios. However, CRISPR‐based Helios‐KO Tregs do not exhibit discernable functional defects, suggesting that Helios does not have a direct role in maintaining Treg stability.