title: TNFRp55 controls regulatory T cell responses in Yersinia-induced reactive arthritis.
abstract: In addition to its well-known pro-inflammatory effects, tumor necrosis factor (TNF) displays anti-inflammatory activities through mechanisms poorly understood. Previously, we reported the development of severe chronic Yersinia enterocolitica-induced reactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. As regulatory T (T(reg)) cells limit chronic inflammation, here we aim to investigate the expansion and function of CD4(+)CD25(+)FoxP3(+) T(reg) cells in the ReA animal model. The number of T(reg) cells as well as the FoxP3 mRNA expression and interleukin (IL)-10 levels were significantly decreased in joint regional lymph nodes (RLNs) of TNFRp55(-/-) mice vs wild-type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, the number of T(reg) cell in TNFRp55(-/-) was similar to WT mice. To explore the in vivo function of T(reg) cells at this chronic phase in WT and TNFRp55-deficient mice, we adoptively transferred CD4(+) T cells from TNFRp55-deficient mice of day 21, into naïve WT or TNFRp55(-/-) mice. When knockout mice were used as recipients we observed higher delayed-type hypersensitivity (DTH) responses and joint inflammation after heat-killed Yersinia (HKY) stimulation. Accordingly, we found higher levels of IL-17, interferon (IFN)-γ, IL-6, transforming growth factor (TGF)-β1 and IL-12/23p40 and lower IL-10 levels in RLN of paws challenged with HKY in TNFRp55(-/-) recipient mice. In addition, we found that CD4(+) T cells from TNFRp55(-/-) mice controlled antigen-specific IL-12/23(p40) production in recipient WT mice. Our results show that TNFRp55 controls the induction and function of T(reg) cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.
authors.affiliation: Division of Immunology, Faculty of Chemistry, Biochemistry and Pharmacy, National University of San Luis, San Luis, Argentina.
authors.forename: Ethelina
authors.initials: E
authors.lastname: Cargnelutti
authors.forename: José L
authors.initials: JL
authors.lastname: Arias
authors.forename: Susana R
authors.initials: SR
authors.lastname: Valdez
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.forename: María S
authors.initials: MS
authors.lastname: Di Genaro
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016918:Arthritis, Reactive / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007596:Joints / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D009092:Mucous Membrane / Q000378:metabolism; D000091402:Prohibitins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D053319:Tumor Necrosis Factor Decoy Receptors / Q000172:deficiency / Q000378:metabolism*; D015007:Yersinia / Q000276:immunology*; D015009:Yersinia Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; C000717331:PHB2 protein, human; D000091402:Prohibitins; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D016753:Interleukin-10; D018664:Interleukin-12; C069521:recombinant human tumor necrosis factor-binding protein-1