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Abstract Number: 600

Regulatory T Cells in Spondyloarthritis (SpA) Animal Model and Modulatory Role of Inducible Costimulator (ICOS)

Luiza Krause1, Ingrid Fert1, Karine Labroquère2, Muriel Andrieu2, Gilles Chiocchia3 and Maxime A. Breban4, 1Immunology and Hematology Department, Institut Cochin - INSERM U1016 - CNRS (UMR 8104)-Université Paris Descartes (UMR-S 1016), Paris, France, 2Cochin Immunobiology Facility, Paris, France, 3Versailles Saint Quentin en Yvelines University, INSERM U987, UFR des Sciences de la Santé, Montigny-le-Bretonneux, France, 4Rheumatology Division, Ambroise Paré Hospital (AP-HP), and Versailles Saint Quentin en Yvelines University, Boulogne-Billancourt, France

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: interleukins (IL), regulatory cells and spondylarthropathy

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Session Information

Session Title: Spondylarthritis and Psoriatic Arthritis - Pathogenesis, Etiology

Session Type: Abstract Submissions (ACR)

Background/Purpose:

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.

Methods:

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.

Results:

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.

Conclusion:

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.


Disclosure:

L. Krause,
None;

I. Fert,
None;

K. Labroquère,
None;

M. Andrieu,
None;

G. Chiocchia,
None;

M. A. Breban,
None.

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