Altered T cell plasticity favours Th17 cells in early arthritis.

OBJECTIVES: The predominance of differentiated Th17 cells has been implied as a key driver of autoimmune arthritis, including early RA. Because accumulating evidence suggests that Th cell differentiation is a plastic process, we investigated plasticity and underlying molecular mechanisms to address the shift towards the Th17 phenotype in early RA. METHODS: A cohort of 61 patients with early, active, untreated RA and 45 age- and sex-matched healthy controls were studied. Viable in vitro- and in vivo-generated Th1, Th2 and Th17 cells were FACS-sorted and transdifferentiated under Th1-, Th2- or Th17-inducing conditions. The cytokine Th profile of the transdifferentiated cells was assessed by flow cytometry. Th cell-associated cytokine and transcription factor gene loci were analysed by chromatin immunoprecipitation assay and their expression by quantitative real-time PCR. RESULTS: In vitro-generated Th cells showed substantial plasticity, which was similar between RA and healthy controls, whereas in vivo-derived Th1 and Th2 cells from RA patients demonstrated an enhanced plasticity towards IL-17-expressing phenotypes compared with healthy controls. Further, in vivo-generated Th17 cells from RA patients showed a resistance to transdifferentiate into Th1 or Th2 cells. The serum/glucocorticoid-regulated kinase 1-forkhead box protein O1-IL-23 receptor (SGK1-FOXO1-IL-23R) axis together with increased RORC expression was associated with the predominant Th17 phenotype in early RA. CONCLUSIONS: Our data indicate that in vivo-originated Th subsets are prone to Th17 cell transdifferentiation in early RA, while Th17 cells are resistant to changes in their phenotype. Together, the data imply that an altered plasticity contributes to the Th17 shift in early RA.

Increased plasticity of non-classic Th1 cells toward the Th17 phenotype.

Objectives: To analyze occurrence and plasticity of two recently described distinct subtypes of Th1 cells named classic (CD161-/CCR6-) and non-classic (CD161+/CCR6+) Th1 cells in early rheumatoid arthritis (RA) patients and healthy controls (HCs).Methods: Frequencies of in vivo-generated Th1 cell populations were assessed after cytokine secretion assay for IFNγ/IL-17 and surface staining for CD161/CCR6. Viable Th1 cells (IFNγ+IL-17-) were sorted into classic Th1 (CD161-CCR6-) and non-classic Th1 (CD161+CCR6+) cells, trans-differentiated under different Th cell-inducing conditions, and assessed for plastic changes by analyzing the Th cell-associated cytokine and transcription factor profiles.Results: Ex vivo frequencies of classic (CD161-CCR6-) and non-classic (CD161+CCR6+) Th1 cells as well as related Th1 cell subpopulations CD161+CCR6- and CD161-/CCR6+ did not differ significantly between RA and HCs. However, trans-differentiation of ex vivo non-classic (CD161+CCR6+) and CD161-/CCR6+ Th1 cells resulted in a substantial shift toward Th17 and Th1/Th17 phenotypes, particularly under Th17-inducing conditions. In contrast, classic (CD161-/CCR6-) and CD161+CCR6- Th1 cells showed higher plasticity towards IL-4-producing cells, most of them shifting to a Th1/Th2 phenotype.Conclusion: Whereas non-classic (CD161+/CCR6+) and CD161-CCR6+ Th1 cells demonstrated an increased plasticity towards IL-17- phenotypes, classic Th1 and CD161+CCR6- Th1 cells showed more plasticity towards IL-4-producing phenotypes.