Session Information
Session Title: T cell Biology and Targets in Autoimmune Disease
Session Type: Abstract Submissions (ACR)
Background/Purpose
Whereas T helper (Th) cell subsets were previously regarded as irreversibly differentiated endpoints, evidence suggests that Th cell differentiation is a plastic process in response to appropriate stimulation. Mechanisms leading to the pathogenetic important predominance of Th17 cells in rheumatoid arthritis (RA) are not yet understood. We hypothesized that an altered T cell plasticity contributes to the shift towards the Th17 phenotype in RA.
Methods
A unique cohort of 35 patients with early, active and untreated RA (to exclude effects of immunosuppressive drugs on T cells) and 33 age- and sex- matched healthy controls (HC) were studied. Viable in vivo-originated Th1, Th2 and Th17 cells were FACS-sorted and trans-differentiated under Th1-, Th2- or Th17-inducing conditions. The cytokine secretion profile of the trans-differentiated cells was assessed by flow cytometry. Analysis of histone modifications in IL17 and RORC gene loci was performed by ChiP assay. The relative expression of cytokine and transcription factor genes was measured by qRT-PCR.
Results
Of interest, Th17 cells from RA patients demonstrated a strikingly diminished re-differentiation capacity into both Th1 and Th2 directions. Under Th1 conditions, RA Th17 cells retained significantly more IL-17-producing cells, whereas frequencies of newly generated Th1 cells in RA were diminished. Similarly, under Th2 conditions, frequencies of newly generated Th2 cells were significantly reduced in RA. Vice versa, RA Th1 and Th2 cells demonstrated an enhanced capacity to re-differentiate into Th17 cells. In order to analyze underlying mechanisms leading to increased re-differentiation of Th1 to Th17 cells in RA, expression of RORC was investigated. We found that RORC expression was higher after re-differentiation of Th1 cells. Moreover, in the IL17 and RORC loci an overrepresentation of the permissive histone modification H3 actetylation over the repressive H3K27 methylation was found in T cells from RA patients. Investigation of the SGK1/ FOXO1/ IL23R pathway, known to be important for Th17 stability, revealed higher expression of SGK1 and IL23R in RA after re-differentiation of sorted Th1 cells.
Conclusion
Together these data indicate that in RA in vivo-originated Th17 cells are resistant to changes in their phenotype, whereas other Th subsets are prone to Th17 cell re-differentiation. Increased RORC expression and the presence of a permissive histone modification state at the RORC gene locus might contribute to the altered Th plasticity in RA, thereby forcing Th17 cell-mediated immunity of the disease.
Disclosure:
J. Leipe,
None;
F. Pirronello,
None;
S. Hermann,
None;
M. Witt,
None;
H. Schulze-Koops,
None;
A. Skapenko,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-plasticity-of-inflammatory-cd4-t-cells-contributing-to-th17-shift-in-rheumatoid-arthritis/