Session Type: Abstract Submissions (ACR)
HLA-B27/human β2m transgenic rats (B27-rats), a model of SpA develop spontaneous colitis and arthritis. It was recently shown in this model that IL-17 producing T cells are expanded both in mesenteric and popliteal lymph nodes (LN). Moreover, after in vitro stimulation, Th17 cells were preferentially induced and expanded by DCs from B27-rats (A&R 2012;64:110-20). Given that regulatory T cells (Treg) and Th17 cells have been described as two distinct subsets with opposing effects on inflammatory disorders, we hypothesized that the Th17 bias observed in B27-transgenic rats could be explained by a decreased frequency and/or a functional defect of Treg cells.
We examined the phenotype and function of Treg in the LN of B27- and control nontransgenic (NTG) rats, using the following methods: cell surface expression of Treg-associated markers; in vitro suppression assay; intra-cellular IL-17 and IL-10 production by flow cytometry and RT-PCR assay of ex vivo-sorted Treg cells; differentiation of naives T cells into Treg in Treg-polarizing conditions and transcription factor expression by RT-PCR.
Based on the combination of Foxp3 and CD25 expression, two suitable markers for Treg in the rat, we distinguished two populations of CD4+ LN T cells, namely regulatory CD25+Foxp3+ T cells (Treg) and activated CD25+Foxp3- T cells (Teff). We observed that Teff cells were specifically enriched in the B27-rats. However, accumulation of Teff cells was not correlated with a defect in Treg differentiation, since we observed similar differentiation of naives Tcells to Treg in Treg-polarizing conditions, in both NTG and B27-rats. Despite a decreased proportion of Treg their suppressive activity was not compromised in the B27-rats. Indeed, Treg from NTG and B27-rats inhibited T cell proliferation to a similar extent. Cell surface expression of several Treg markers, i.e. GITR, CTLA-4 and LAG-3 was equivalent between NTG and B27-rats. In contrast, we observed an up-expression of ICOS marker in Treg cells from B27-rats, as compared to NTG-rats. High levels of ICOS expression usually define a population of Treg that present superior suppressive activity and expression of IL-10. Paradoxically, we observed that Treg from B27-rats down-expressed IL-10, as compared to those from NTG rats. Furthermore, Treg from B27-rats expressed higher levels of IL-17 than those from control rats. Interestingly, anti-ICOS mAb blocking assay resulted in a decrease of IL-17 expression and increase of IL-10 expression by naive or effector CD4+ T cells cocultured with DCs from B27-rats.
Our data suggest that an IL-10/IL-17 imbalance observed in Treg from B27-rats may contribute to disease development and reveal a critical role for ICOS signaling in the generation and maintenance of IL-17 producing T cells in this animal model of SpA.
M. A. Breban,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/regulatory-t-cells-in-spondyloarthritis-spa-animal-model-and-modulatory-role-of-inducible-costimulator-icos/