Background/Purpose: Mechanisms underlying the predominance of Th17 cells observed in 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 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 IFNγ and IL-17 and surface staining for CD161 and CCR6. Viable Th1 cells (IFNγ+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 ex vivoby analyzing the cytokine and transcription factor profile by flow cytometry on the protein and by qPCR on the mRNA level.

Results: Trans-differentiation of non-classic Th1 cells under inflammatory Th17-inducing conditions resulted in markedly high frequencies of IL-17-producing cells, Th17 cells and Th1/Th17 cells (IL-17+IFNγ+), whereas no substantial plasticity towards a Th17 phenotype was observed for classic Th1 cells (Th17 cells: 3.9% vs 0.9%, p=0.045; Th17/Th1 cells: 16.6% vs. 0.9%, p=0.00003). In marked contrast, classic Th1 cells showed higher plasticity towards IL-4-producing cells, most of them being Th1/Th2 cells (IFNγ+/IL-4+), compared to non-classic Th1 cells (Th1/Th2 cells: 8.4% vs. 3.0%, p=0.015). Consistently, for RORC higher expression was found in non-classic Th1 and for GATA-3 in classic Th1 cells ex vivo. The frequencies of classic and non-classic Th1 cells did not differ significantly between RA patients and healthy individuals.

Conclusion: Non-classic Th1 cells demonstrate a general substantial plasticity towards the Th17 phenotype, which might contribute to their pathogenicity, whereas classic Th1 cells show the propensity to acquire a Th2 phenotype and might therefore give rise to a less pathogenic phenotype. Similar frequencies of ex vivo non-classic and classic Th1 cells between RA and HC suggest a conserved phenotype of the populations after their in vivo generation and might argue against the contribution of non-classic Th1 cells to Th17-biased RA phenotype.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/increased-plasticity-of-non-classic-th1-cells-towards-the-th17-phenotype/