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Foxp3+ Helios+ regulatory T cells are expanded in active systemic lupus erythematosus
  1. Tobias Alexander1,2,
  2. Arne Sattler3,
  3. Lars Templin1,
  4. Siegfried Kohler4,
  5. Christian Groß5,
  6. Andreas Meisel3,
  7. Birgit Sawitzki6,
  8. Gerd-Rüdiger Burmester1,
  9. Renate Arnold7,
  10. Andreas Radbruch2,
  11. Andreas Thiel8,
  12. Falk Hiepe1,2
  1. 1Medical Department, Division of Rheumatology and Clinical Immunology, Charité–University Medicine, Berlin, Germany
  2. 2German Rheumatism Research Center (DRFZ) Berlin, Berlin, Germany
  3. 3Nephrology and Internal Intensive Care Unit, Berlin–Brandenburg Center for Regenerative Therapies (BCRT), Charité–University Medicine, Berlin, Germany
  4. 4Department of Neurology with Chair in Experimental Neurology, Charité–University Medicine, Berlin, Germany
  5. 5Clinic for Orthopaedics, Center for Musculoskeletal Surgery, Charité–University Medicine, Berlin, Germany
  6. 6Institute for Medical Immunology, Charité–University Medicine, Berlin, Germany
  7. 7Medical Department, Division of Hematology, Oncology and Tumor Immunology, Charité–University Medicine Berlin, Berlin, Germany
  8. 8Department of Regenerative Immunology and Aging, Charité–University Medicine Berlin, Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany
  1. Correspondence to Tobias Alexander, Medical Department, Division of Rheumatology and Clinical Immunology, Charité–University Medicine Berlin, Charitéplatz 1, Berlin 10117, Germany; tobias.alexander{at}charite.de

Abstract

Objectives Recent data debate the suitability of Helios, an Ikaros family member, as a marker for thymic-derived regulatory T cells (Treg). Nevertheless, Foxp3+ Helios+ Treg may be of particular relevance in mediating immune tolerance in chronic autoimmunity, such as systemic lupus erythematosus (SLE), as they possess enhanced suppressive function, compared to Foxp3+ Helios Treg.

Methods Multicolour flow cytometry was performed to analyse Foxp3 and Helios expression in peripheral blood CD4 T cells from SLE patients, compared to healthy controls (HC) and systemic sclerosis (SSc) and rheumatoid arthritis (RA) patients. Cytokine production, chemokine receptor expression for CXCR3 and CCR4, basal signal transducer and activator of transcription 5 (STAT5)a phosphorylation levels and T-cell receptor (TCR) Vβ repertoire were analysed by flow cytometry, and the methylation status of the Foxp3 locus (Treg-specific demethylated region, TSDR) by real-time PCR.

Results Frequencies of Foxp3+ Helios+ Treg, unlike Foxp3+ Helios T cells, were significantly increased in SLE patients and positively correlated with disease activity, whereas they were unaltered in SSc and RA patients. Compared to HC, Foxp3+ Helios+ Treg in SLE predominantly displayed a CD45RA/CD31/FoxP3low memory phenotype with increased Ki-67 expression, enhanced basal pSTAT5a levels and a restricted TCR repertoire. Nonetheless, similar to HC, Foxp3+ Helios+ Treg in SLE lacked effector cytokine production, possessed a highly demethylated TSDR and expressed comparable levels of CXCR3 and CCR4.

Conclusions Our data suggest that Helios-expressing Foxp3+ Treg with functional suppressive capacity and migratory potential into inflamed tissues are expanded in active SLE, presumably through γ-chain signalling cytokines and TCR stimulation, to compensate for autoreactive effector responses.

  • Systemic Lupus Erythematosus
  • Autoimmunity
  • T Cells
  • Autoimmune Diseases

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