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

CARGNELUTTI E.; ARIAS JL.; VALDEZ S; GABRIEL A. RABINOVICH; DI GENARO M.S.

IMMUNOLOGY AND CELL BIOLOGY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2013 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 enterocolitica-induced 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 CD4posCD25posFoxP3pos Treg cells in the ReA animal model. The number of Treg 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 Treg cell in TNFRp55-/- was similar to WT mice. To explore the in vivo function of Treg cells at this chronic phase in WT and TNFRp55-deficient mice, we adoptively transferred CD4pos T cells from TNFRp55-deficient mice of day 21, into naı¨ve 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)-gamma, IL-6, transforming growth factor (TGF)-b1 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 CD4pos 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 Treg cells through differential regulation of cytokine production, suggesting a novel molecular target for immune intervention in ReA.