OBJECTIVES: 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.