Session Title: T Cell Biology and Targets in Autoimmune Disease Poster II
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: IL-1β blockade is a highly effective therapy for systemic juvenile idiopathic arthritis (sJIA). However, the rate of inactive disease attained in these trials is lower than reported in sJIA patients treated with IL-1 blockade at disease onset. We have hypothesized that sJIA is a biphasic process in which an initial IL-1β-driven systemic phase directly promoting Th17 differentiation from both Th0 and T regulatory T (Treg) cells and gives rise to IL-17-driven chronic inflammatory arthritis. We sought to test this hypothesis in the IL-1ra-/- model, a spontaneous T cell-mediated murine arthritis dependent upon both IL-1β and IL-17.
Methods: Synovial tissue, lymph nodes and spleen from Il-1ra-/- were characterized via flow cytometry for FOXP3, RORγt expression and cytokine production. In addition, we examined the transcriptomic landscape of sorted Treg cells from newly generated IL-1ra-/- Foxp3-eGFP mice and WT Foxp3-eGFP controls. We sorted 50,000 WT and IL-1ra-/- Treg cells from 3 mice and performed low-input RNA-Sequencing. Differential expression testing was performed using EdgeR. Additionally, we performed Gene Set Enrichment Analysis between WT and IL-1ra-/- groups. In order to assess osteoclastogenic potential, sorted Treg cells where co-culture with macrophage precursors cells (1:2 ratio) in presence of anti-CD3/CD28 beads, M-CSF and RANK-L. After 5 days of co-culture, TRAP+ multinucleated cells (more than three nuclei) were counted.
Results: The percentage of Treg cell among CD4+ cells in periphery and locally in synovial tissue was similar between WT and IL-1ra-/- mice. However, Treg cells from IL-1ra-/- synovium showed an up-regulation of RORγt expression. Interestingly, a significant number of FOXP3+ cells also produced IL-17 upon in vitro stimulation. To gain molecular insight into the mechanism underlying Treg cell plasticity in our model, we performed RNAseq-driven characterization of Treg cells from IL-1ra-/- and WT mice. Notably, Gene Set Enrichment Analysis revealed distinct metabolic programs between both subsets. The oxidative phosphorylation gene set was enriched in WT Treg. On the other hand, mTOR and glycolysis pathways that orchestrate a metabolic checkpoint for the differentiation of Th17 cells were enriched in IL-1ra-/- Treg cells. This finding confirms the ongoing conversion of Foxp3+ cells into Th17 cells. In addition to this Th17-skewed phenotype, Treg from IL-1ra-/- mice over-expressed RANK-L and facilitate osteoclastogenesis in vitro whereas WT Treg inhibited osteoclast differentiation, suggesting a novel pathogenic role for IL-1ra-/- Treg cells.
Conclusion: All together our results suggest that chronic inflammatory arthritis in IL-1ra-/- mice is associated with the conversion of Foxp3+ Treg cells into pathogenic Th17 cells. These findings suggest that early IL-1β blockade could modulate the development of arthritogenic T cells in IL-1-driven arthritis, a result that may inform the understanding and treatment of sJIA.
To cite this abstract in AMA style:Levescot A, Nelson-Maney N, Morris A, Grieshaber Bouyer R, Lee P, Nigrovic P. Autoimmune Arthritis in IL-1 Receptor Antagonist-Deficient Mice Is Associated with a Pathogenic Conversion of Foxp3+ Regulatory T Cells into Th17 Cells [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/autoimmune-arthritis-in-il-1-receptor-antagonist-deficient-mice-is-associated-with-a-pathogenic-conversion-of-foxp3-regulatory-t-cells-into-th17-cells/. Accessed September 20, 2020.
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