Co-expression of Foxp3 and Helios facilitates the identification of human T regulatory cells in health and disease

• Published in: Frontiers in immunology Vol. 14; p. 1114780
• Main Authors: Morina, Lyra, Jones, Madalyn E., Oguz, Cihan, Kaplan, Mariana J., Gangaplara, Arunakumar, Fitzhugh, Courtney D., Kanakry, Christopher G., Shevach, Ethan M., Buszko, Maja
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 07.06.2023
• Subjects: Animals; COVID-19 - metabolism; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3; Graft vs Host Disease - metabolism; GVHD; Helios; Humans; Immunology; Mice; Receptors, Antigen, T-Cell - metabolism; regulatory T cell; SLE; T-Lymphocytes, Regulatory - metabolism; Transcription Factors - metabolism; Helios; GVHD; regulatory T cell; Foxp3; SLE
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1114780

Foxp3 is regarded as the major transcription factor for T regulatory (T reg ) cells and expression of Foxp3 is used to identify and quantitate Treg cells in mouse models. However, several studies have demonstrated that human CD4 + T conventional (T conv ) cells activated in vitro by T cell receptor (TCR) stimulation can express Foxp3. This observation has raised doubt as to the suitability of Foxp3 as a T reg marker in man. Helios, a member of the Ikaros gene family, has been shown to be expressed by 80-90% of human Foxp3 + T reg cells and can potentially serve as a marker of human T reg . Here, we confirm that Foxp3 expression is readily upregulated by T conv upon TCR stimulation in vitro , while Helios expression is not altered. More importantly, we show that Foxp3 expression is not elevated by stimulation of hT conv in a humanized mouse model of graft versus host disease (GVHD) and in patients with a wide variety of acute and chronic inflammatory diseases including sickle cell disease, acute and chronic GVHD, systemic lupus erythematosus, as well as critical COVID-19. In all patients studied, an excellent correlation was observed between the percentage of CD4 + T cells expressing Foxp3 and the percentage expressing Helios. Taken together, these studies demonstrate that Foxp3 is not induced upon T conv cell activation in vivo and that Foxp3 expression alone can be used to quantitate T reg cells in humans. Nevertheless, the combined use of Foxp3 and Helios expression provides a more reliable approach for the characterization of T reg in humans.