TNFRp55 controls regulatory T cell responses in Yersinia-induced

ETHELINA CARGNELUTTI1,; JOSÉ L. ARIAS; SUSANA R. VALDEZ; GABRIEL A. RABINOVICH; MARÍA S DI GENARO

IMMUNOLOGY AND CELL BIOLOGY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2012 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 enterocoliticainducedreactive arthritis (ReA) in mice lacking the TNF receptor (TNFR)p55. Asregulatory T (Treg) cells limit chronic inflammation, here we aim to investigate theexpansion and function of CD4+CD25+FoxP3+ Treg cells in the ReA animal model. Thenumber of Treg cells as well as the FoxP3 mRNA expression and IL-10 levels weresignificantly decreased in joint regional lymph nodes (RLN) of TNFRp55-/- mice versuswild-type (WT) mice at the arthritis onset. However, at chronic phase of arthritis, thenumber 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, weadoptively transferred CD4+ T cells from TNFRp55-deficient mice of day 21, into naïveWT or TNFRp55-/- mice. When knockout mice were used as recipients we observedhigher delayed-type hypersensitivity (DTH) responses and joint inflammation afterheat-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 pawschallenged with HKY in TNFRp55-/- recipient mice. In addition, we found that CD4+ Tcells from TNFRp55-/- mice controlled antigen-specific IL-12/23(p40) production inrecipient WT mice. Our results show that TNFRp55 controls the induction and functionof Treg cells through differential regulation of cytokine production, suggesting a novelmolecular target for immune intervention in ReA.