TNFRp55 controls regulatory T cell responses in Yersinia-induced reactive arthritis

CARGNELUTTI ETHELINA; ARIAS JOSÉ L; VALDEZ SUSANA R; RABINOVICH G. A; DI GENARO MARÍA SILVIA

IMMUNOLOGY AND CELL BIOLOGY

NATURE PUBLISHING GROUP

Lugar: Melbourne; Año: 2013 vol. 91 p. 159 - 166

0818-9641

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 enterocoliticainduced reactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. As regulatory T (Treg) cells limit chronic inflammation, here we aim to investigate the expansion and function of CD4+CD25+FoxP3+ Treg cells in the ReA animal model. The number of Treg cells as well as the FoxP3 mRNA expression and IL-10 levels were significantly decreased in joint regional lymph nodes (RLN) of TNFRp55-/- mice versus wild-type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, the number of Treg cell in TNFRp55-/- was similar to WT mice. To explore the in vivofunction of Treg 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, IFN-γ, IL-6, 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 inrecipient WT mice. Our results show that TNFRp55 controls the induction and function of Treg cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.