title: Interplay between TNF and regulatory T cells in a TNF-driven murine model of arthritis.
abstract: CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) are involved in several autoimmune diseases, including rheumatoid arthritis. TNF-α blockers induce therapeutic benefits in rheumatoid arthritis via a variety of mechanisms. We aimed to characterize the impact on Treg of TNF-α overexpression in vivo and of TNF-α inhibiting treatments. We used human TNF-α transgenic mice as a model of strictly TNF-α-dependent arthritis. Our study showed that initial Treg frequency was lower in TNF-α transgenic mice than in wild-type mice. However, the course of arthritis was marked by elevation of Treg frequency and a dramatic increase in expression of TNFR2. Antagonizing TNF-α with either the anti-human TNF-α Ab (infliximab) or active immunotherapy (TNF-kinoid) increased the Treg frequency and upregulated CTLA-4, leading to enhancement of suppressor activity. Moreover, both anti-TNF-α strategies promoted the differentiation of a CD62L(-) Treg population. In conclusion, in an in vivo model of TNF-α-driven arthritis, Treg frequency increased with inflammation but failed to control the inflammatory process. Both passive and active TNF-α-inhibiting strategies restored the suppressor activity of Treg and induced the differentiation of a CD62L(-) Treg population.
authors.affiliation: EA4222, Physiopatologie et Biothérapies de la Polyarthrite Rhumatoïde, Sorbonne Paris Cité-Université Paris 13, 93000 Bobigny, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Biton
authors.forename: Luca
authors.initials: L
authors.lastname: Semerano
authors.forename: Laure
authors.initials: L
authors.lastname: Delavallée
authors.forename: Delphine
authors.initials: D
authors.lastname: Lemeiter
authors.forename: Marion
authors.initials: M
authors.lastname: Laborie
authors.forename: Géraldine
authors.initials: G
authors.lastname: Grouard-Vogel
authors.forename: Marie-Christophe
authors.initials: MC
authors.lastname: Boissier
authors.forename: Natacha
authors.initials: N
authors.lastname: Bessis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D002450:Cell Communication / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007116:Immunization, Passive; D016233:Immunotherapy, Active; D000069285:Infliximab; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab