title: An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy.
abstract: OBJECTIVE
  Randomised-controlled trials have recently proven the efficacy of the interleukin (IL)-6 receptor antagonist tocilizumab (TCZ) in giant cell arteritis (GCA). However, the mechanism of action of IL-6 blockade in this disease is unknown. Moreover, the role of regulatory T (Treg) cells in the pathogenesis of GCA remains underexplored. Given the plasticity of Tregs and the importance of IL-6 in their biology, we hypothesised that TCZ might modulate the Treg response in GCA. We therefore characterised the Treg compartment of patients with GCA treated with TCZ.
  
  
  METHODS
  We classified 41 patients with GCA into three groups: active disease (aGCA, n=11), disease remission on corticosteroids (rGCA-CS, n=19) and disease remission on TCZ (rGCA-TCZ, n=11). Healthy controls (HCs) were included for comparison. We determined the frequency, phenotype and function of peripheral blood Tregs.
  
  
  RESULTS
  Patients with aGCA demonstrated a hypoproliferating Treg compartment enriched in IL-17-secreting Tregs (IL-17+Tregs). Tregs in patients with aGCA disproportionally expressed a hypofunctional isoform of Foxp3 that lacks exon 2 (Foxp3Δ2). Foxp3Δ2-expressing Tregs coexpressed CD161, a marker commonly associated with the Th17 linage, significantly more often than full-length Foxp3-expressing Tregs. Compared with those of HCs, GCA-derived Tregs demonstrated impaired suppressor capacity. Treatment with TCZ, in contrast to CS therapy, corrected the Treg abnormalities observed in aGCA. In addition, TCZ treatment increased the numbers of activated Tregs (CD45RA-Foxp3high) and the Treg expression of markers of trafficking (CCR4) and terminal differentiation (CTLA-4).
  
  
  CONCLUSIONS
  TCZ may exert its therapeutic effects in GCA by increasing the proliferation and activation of Tregs, and by reverting the pathogenic Treg phenotype seen during active disease.
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Chie
authors.initials: C
authors.lastname: Miyabe
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Miyabe
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Klemen
authors.initials: K
authors.lastname: Strle
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Kim
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Stone
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.affiliation: Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Unizony
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D060908:CTLA-4 Antigen / Q000032:analysis; D049109:Cell Proliferation; D003430:Cross-Sectional Studies; D005260:Female; D051858:Forkhead Transcription Factors / Q000032:analysis / Q000235:genetics; D013700:Giant Cell Arteritis / Q000097:blood* / Q000188:drug therapy*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000032:analysis; D010641:Phenotype; D054398:Receptors, CCR4 / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D000093242:Interleukin-6 Inhibitors
chemical_list: D000305:Adrenal Cortex Hormones; D000894:Anti-Inflammatory Agents, Non-Steroidal; D061067:Antibodies, Monoclonal, Humanized; D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D055651:NK Cell Lectin-Like Receptor Subfamily B; D054398:Receptors, CCR4; D000093242:Interleukin-6 Inhibitors; C515354:CCR4 protein, human; C418974:FOXP3 protein, human; C508017:IL2RA protein, human; C502936:tocilizumab
keywords: DMARDs (biologic); Giant Cell Arteritis; T Cells; Treatment