Artikel
Plasticity of classic and non-classic Th1 cells towards a Th17 phenotype in RA
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Veröffentlicht: | 1. September 2015 |
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Introduction: Mechanisms underlying the predominance of Th17 cells observed in rheumatoid arthritis (RA) are not fully understood. Th cell plasticity is a potential mechanism leading to enrichment of Th populations under certain conditions. Recently, two distinct subtypes of Th1 cells named classic (IFNγ+RORC-CD161-CCR6-) and non-classic (IFNγ+RORC+CD161+CCR6+) Th1 cells were described. Given that non-classic Th1 cells share several characteristics with Th17 cells, we hypothesized that non-classic Th1 cells might show an enhanced plasticity towards the Th17 phenotype. Increased frequencies of non-classic Th1 cells or an enhanced plasticity to a Th17 phenotype in RA might therefore potentially contribute to the Th17 shift in RA.
Methods: CD4 memory T cells were isolated from patients with early active and untreated RA and age- and sex-matched healthy controls (HC) by MACS. Frequencies of the in vivo-generated Th1 cell populations were assessed after cytokine secretion assay for IFN-γ and IL-17 and surface staining for CD161 and CCR6. Viable Th1 cells (IFN-γ+IL-17-) were FACS-sorted into classic Th1 (CD161-CCR6-) and non-classic Th1 (CD161+CCR6+). Sorted Th1 cell populations were trans-differentiated under Th0-, Th1-, Th2- and Th17-inducing conditions. Plastic changes were assessed by analyzing the cytokine profile (IL-17, IFN-γ, IL-4, IL-9) by flow cytometry after 7 days of trans-differentiation.
Results: Trans-differentiation of non-classic Th1 cells under Th17-inducing conditions resulted in markedly high frequencies of IL-17-producing cells, Th17 cells and Th1/Th17 cells (IL-17+IFNg+), whereas no substantial plasticity towards a Th17 phenotype was observed for classic Th1 cells (Th17 cells: 4.5%±5.2% vs 1.3%±2.8%, p=0.207; Th17/Th1 cells: 14.4%±11.3% vs. 1.2%±1.7%, p=0.018). In marked contrast, classic Th1 cells showed higher plasticity towards IL-4-producing cells, most of them being Th1/Th2 cells (IFN-γ+/IL-4+), compared to non-classic Th1 cells under Th17-inducing conditions (Th1/Th2 cells: 5.5%±4.2% vs. 2.6%±3.1%, p=0.172). The ex vivo frequencies of classic and non-classic Th1 cells did not differ significantly between RA patients and healthy individuals.
Conclusion: Although non-classic Th1 cells demonstrated a substantial plasticity towards the Th17 phenotype, similar frequencies of this cell population in RA and HC argue against the contribution of non-classic Th1 cells to Th17-biased RA phenotype. Further investigations are necessary to clarify the issue.