Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: CD4+FoxP3+ regulatory T cells (Tregs) are essential for maintaining immune homeostasis, and are functionally defective in rheumatoid arthritis (RA) and other chronic inflammatory diseases. In RA, effective anti-TNF treatment was found to modify Tregs phenotype and restore their suppressive function. Tregs express the two TNF receptors (TNFR): TNFR1 and TNFR2. Nevertheless, the respective roles of TNFR1 and TNFR2 in mediating the effect TNF on Tregs are still unclear. Likewise, whether TNF blockade may affect Tregs via the TNF receptors, is not clearly established. To dissect the role of the TNF-TNFR2 system on Tregs in chronic inflammatory diseases by : 1) determining the effect of the interaction between TNF and TNFR2 on cultured mouse Tregs 2) studying the effect of TNFR2 deficiency in a model of chronic inflammation 3) analyzing the influence of anti-TNF therapy on TNFR2 expression on Tregs in RA patients
Methods: Tregs were purified by magnetic separation from mice spleen and their frequencies and phenotype were analyzed by flow cytometry. TNFR2 deficient mice were used. Psoriasis-like skin inflammation was induced by imiquimod skin application. Tregs from blood of RA patients were studied by flow cytometry.
Results: TNF induces Foxp3 maintenance in cultures of purified mouse Tregs. With two models of TNFR2 inactivation (a TNFR2-blocking antibody and a TNFR2 knock-out mouse) we showed that this effect was mediated by TNF-TNFR2 -and not TNFR1- interaction. Moreover, compared to Tregs from wild type (WT) mice, TNFR2-deficient Treg showed reduced suppression of effector T cells (Teff) proliferation and Teff interferon-g production. TNF decreased CD39 expression and ATP hydrolysis activity in cultured Tregs. Additionally, TNFR2-deficient Tregs were less effective in hydrolyzing ATP than Tregs from WT mice. In parallel, we evaluated the consequences of TNFR2 deficiency in a model of skin inflammation, namely imiquimod-induced psoriasis. In TNFR2- deficient mice, Tregs frequencies were lower and the clinical signs of psoriasis were aggravated, compared to WT mice. Moreover, in the peripheral blood of RA patients treated with anti-TNF agents there was both an increase in total Tregs frequencies, and in the frequency of Tregs expressing TNFR2 at 3 months of treatment vs. the baseline.
Conclusion: The integrity of the TNF-TNFR2 system is critical for Treg survival and suppressive activity in vitro. TNFR2 deficiency aggravates a model of chronic skin inflammation. Three-month anti-TNF treatment is associated with an increase of TNFR2-expressing Tregs in the peripheral blood of RA patients. These data suggest that the effect of TNF blockade on Tregs may rely on the activation of the TNF-TNFR2 system.
To cite this abstract in AMA style:Santinon F, Batignes M, Breckler M, Herve R, Caux F, Decker P, Boissier MC, Semerano L, Bessis N. Tumor Necrosis Factor Receptor 2 Is Crucial for Regulatory T Cells Activity with Consequences in a Model of Chronic Inflammation and in Anti-TNF Treated Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/tumor-necrosis-factor-receptor-2-is-crucial-for-regulatory-t-cells-activity-with-consequences-in-a-model-of-chronic-inflammation-and-in-anti-tnf-treated-rheumatoid-arthritis/. Accessed February 18, 2020.
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