An expanded population of pathogenic regulatory T cells in giant cell arteritis is abrogated by IL-6 blockade therapy

Abstract

Objectives Randomized-controlled trials have recently proven the efficacy of the interleukin-6 receptor antagonist tocilizumab (TCZ) in GCA. However, the mechanism of action of IL-6 blockade in this disease is unknown. Moreover, the role of regulatory T-cells (Treg) in the pathogenesis of GCA remains underexplored. Given the plasticity of Tregs and the importance of IL-6 in their biology, we hypothesized that TCZ might modulate the Treg response in GCA. We therefore characterized the Treg compartment of GCA patients treated with TCZ Methods We classified 41 GCA patients into 3 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 were included for comparison. We determined the frequency, phenotype and function of peripheral blood Tregs. Results aGCA patients demonstrated a hypoproliferating Treg compartment enriched in IL-17-secreting Tregs (IL-17+Tregs). Tregs in aGCA patients disproportionally expressed a hypofunctional isoform of Foxp3 that lacks exon 2 (Foxp3Δ2). Foxp3Δ2-expressing Tregs co-expressed CD161, a marker commonly associated with the Th17 linage, significantly more often than full-length Foxp3-expressing Tregs. Compared to those of healthy controls, 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.

New insights into the pathogenesis of giant cell arteritis

“…A dysfunctional Tregs response has been also implicated in GCA pathogenesis based on the demonstration of a reduced Treg cells frequency in the peripheral blood of GCA patients and the absence of any modulation of Treg cell frequency by steroid treatment [79]. Interestingly, the expression of Foxp3, the master regulator of Tregs is increased in GCA arteries [79,82]. Since that Treg cells display a remarkable functional plasticity, it might be possible that artery Tregs may not be suppressive actually producing Th1 or Th17 cytokines.…”

Regulatory T Cells and Profile of FOXP3 Isoforms Expression in Peripheral Blood of Patients with Myelodysplastic Syndromes

“…Here we need to make a significant remark. In our previous studies, we classified Treg subpopulations as FOXP3 exon 2 + and exon 2 − [ 22 , 23 ] as some other investigators did [ 24 – 26 ]. Now we consider that it was incorrect.…”

Dawn of Monitoring Regulatory T Cells in (Pre-)clinical Studies: Their Relevance Is Slowly Recognised

“…This can be acceptable, but using cells from patients may have added value when the disease has impaired the intrinsic function of the cells. For example, patients with giant cell arteritis can have a defect in their FoxP3 protein, which affects the suppressive capacity of the Tregs, but could be pharmacologically corrected (114).…”