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

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)-ß1 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.

Lack of TNFR p55 results in heightened expression of IFN-γ and IL-17 during the development of reactive arthritis.

Reactive arthritis (ReA) is a type of arthritis originating from certain gastrointestinal or genitourinary infections. In previous studies, we reported the development of progressive Yersinia enterocolitica-induced ReA in mice lacking TNFR p55; however, the mechanisms underlying this effect are still uncertain. In this study, we investigated the impact of TNFR p55 deficiency in modulating Ag-specific Th1 and Th17 responses during this arthritogenic process. We found more severe ReA in TNFRp55(-/-) mice compared with their wild-type (WT) counterparts. This effect was accompanied by increased levels of Yersinia LPS in the joints of knockout mice. Analysis of the local cytokine profile revealed greater amounts of IFN-γ and IL-17 in arthritic joints of TNFRp55(-/-) mice compared with WT mice at day 21 postinfection. Moreover, altered IL-17 and IFN-γ production was observed in mesenteric and inguinal lymph nodes of Yersinia-infected TNFRp55(-/-) mice, as well as in spleen cells obtained from infected mice and restimulated ex vivo with bacterial Ags. Increased levels of cytokine secretion were associated with a greater frequency of CD4(+)IL-17(+), CD4(+)IFN-γ(+), and IL-17(+)IFN-γ(+) cells in TNFRp55(-/-) mice compared with WT mice. Remarkably, Ab-mediated blockade of IL-17 and/or IFN-γ resulted in reduced joint histological scores in TNFRp55(-/-) mice. A mechanistic analysis revealed the involvement of p40, a common subunit of heterodimeric IL-12 and IL-23, in the generation of augmented IFN-γ and IL-17 production under TNFR p55 deficiency. Taken together, these data indicate that, in the absence of TNFR p55 signaling, Th1 and Th17 effector cells may act in concert to sustain the inflammatory response in bacterial-induced arthritogenic processes.

IFN-gamma plays a detrimental role in murine defense against nasal colonization of Staphylococcus aureus.

The anterior nares are the major reservoir in humans of Staphylococcus aureus with the risk of developing endogenous infections or transmitting infections to susceptible persons. The mechanisms that mediate attachment of staphylococci to the nasal mucosa are little known. The purpose of the present work was to study some factors that could influence the nasal colonization in an animal model of mice. We investigated the possible role of IFN-gamma. We used S. aureus ATCC 35556 (SA113) slime-producing and ATCC 25923 non-slime-producing strains. Male 6-week-old BALB/c, C57BL/6 (wild-type, WT), and gene-deficient IL-12p40 (IL-12p40-/-) or IL-4 (IL-4-/-) mice on C57BL/6 background were infected with a dose of S. aureus of 10(6) CFU in 10mul of saline. The total number of S. aureus CFU per nose and lung, specific IgA response and IFN-gamma levels were evaluated. Significant higher CFU were recovery from the narines of C57BL/6 compared with BALB/c mice either after ATCC 35556 (p<0.0001) and ATCC 25923 (p<0.02) strain infection. Low IgA response correlated with high bacterial counting in the C57BL/6 nasal region. Moreover, C57BL/6 mice showed major colonization of slime-producing S. aureus ATCC 35556 than non-slime-producing ATCC 25923 S. aureus strain (p<0.02). IL-12p40-/-mice clarified the bacteria from their nose more efficiently that WT mice after slime-producing S. aureus (p<0.0001). Accordingly, significant lower level of IFN-gamma were detected in IL-12p40-/- compared with WT mice after infection with this strain (p<0.03). The results suggested the influence of the slime production in nasal colonization of S. aureus, and indicate at first time that IFN-gamma may play a detrimental role in this mucosal infection. These results could contribute to elucidate mucosal immune mechanisms involved in S. aureus colonization and then control infections in susceptible persons.