T‐cell‐specific deletion of gp130 renders the highly susceptible IL‐10‐deficient mouse resistant to intestinal nematode infection

Abstract

Gp130 is the common receptor of the IL-6 family of cytokines and is involved in many biological processes, including acute phase response, inflammation and immune reactions. To investigate the role of gp130 under inflammatory conditions, T-cell-specific conditional gp130 mice were first bred to the IL-10-deficient background and were then infected with the gastrointestinal nematode Trichuris muris. While IL-10 À/À mice were highly susceptible to T. muris, developed a mixed Th1/Th17 response and displayed severe inflammation of the caecum, infection of mice with an additional T-cell-specific deletion of gp130 signalling completely reversed the phenotype. These mice showed an accelerated worm expulsion that was associated with the rapid generation of a strong Th2 immune response and a significant increase in Foxp3-expressing Treg. Therefore, gp130 signalling in T cells regulates a switch between proinflammatory and pathogenic Th1/Th17 cells and regulatory Th2/Treg in vivo. Taken together, the data demonstrate that gp130 signalling in T cells is a positive regulator of inflammatory processes, favouring the Th1/Th17 axis.Key words: Cytokine receptor . Helminthic infection . Inflammation Th1/Th2/Th17 cells Transgenic mice IntroductionThe common receptor gp130 is constitutively expressed on immune and non-immune cells and is used by all members of the IL-6 family, which comprises IL-6, IL-11, leukaemia inhibitory factor, oncostatin M and the recently characterized cytokine IL-27, among others [1,2]. While gp130 acts as the obligate signalling subunit, each cytokine first binds to its specific receptor, which accounts for the difference in activities [3,4]. The lethality of mice with classical disruptions of two gp130 alleles demonstrated that gp130 signalling is important for the development of the nervous and hematopoietic systems [5,6]. Moreover, signals mediated by gp130 regulate multiple other biological functions, including acute phase response, immune reactions and inflammation [7,8]. The receptor is also involved in sustaining the disease state in inflammatory bowel disease, rheumatoid arthritis (RA) or MS [9][10][11]. The Th pathway is composed of, at least, three distinct subsets: Th1 cells produce IFN-g and are involved in the fight against intracellular pathogens. The Th2 immune response with T cells producing IL-4, IL-5 and IL-13 provides immunity to helminths [2]. Th17 cells produce cytokines like IL-17, IL-22 and mediate immunity to extracellular bacteria and fungi, but are also responsible for autoimmunity and inflammation [12,13]. Development of naïve T cells to Th17 cells requires the presence of IL-6, TGF-b1 and the transcription factor RORgt [14][15][16][17]. [20,21]. Since TGF-b1 is a common factor for Treg and Th17 cells, it is possible that a switch from Th17 to Treg exists in vivo in the absence of IL-6 signalling in T cells. The gastrointestinal helminth Trichuris muris is a good model to investigate Th-cell pathways. In common inbred mouse strains (BALB/c, C57BL/6), infection with T. muris is...

Interleukin-10 Signaling in Regulatory T Cells Is Required for Suppression of Th17 Cell-Mediated Inflammation

“…In contrast to immuno-suppressive effects of IL-10, IL-6 signaling on T cells has been suggested to be critical for mediating as well as sustaining enteric inflammation (Fasnacht et al, 2009). To identify if IL-6 signaling plays a similar role in Treg cells, we examined Foxp3 Cre Il6ra fl/fl mice.…”

Cell-Intrinsic gp130 Signaling on CD4+ T Cells Shapes Long-Lasting Antiviral Immunity

“…However, flow cytometric analysis of IgG 2a/c expression on B cells revealed a profound reduction in the proportion of isotype-switched IgD − IgM − B cells that were IgG 2a/c + in the absence of T cell specific gp130 at day 12 after ARM infection (Figure 3c). Skewing of antibody responses from IgG 2a toward IgG 1 has commonly been associated with increased Th2 immunity, and gp130 signaling has previously been reported to enhance Th2 to immune responses (27). However, we found that after LCMV ARM infection the expression of Gata3 , the canonical transcription factor associated with Th2 differentiation, was not significantly altered in FACS isolated T EFF , T FH and virus specific (I-A b GP 67–77 + ) CD4 + T cells in the absence of gp130 (Figure 3d).…”

“…It has previously been shown that T cell specific deletion of gp130 during infection with gastrointestinal nematode Trichuris muris strongly polarizes the immune responses away from pathogenic Th1/Th17 responses towards protective Th2 responses (27). In the strongly Th1 environment of LCMV ARM infection we found little evidence of increased Th2 cell differentiation in the absence of gp130.…”

Immunity to Helminths: Resistance, Regulation, and Susceptibility to Gastrointestinal Nematodes

“…The DEREG studies suggest that they are not, or at least that compensatory populations can come in and function in their absence. The CD4 + T cell does appear to be the critical source required for controlling intestinal pathology, however (192). In terms of IL-10 control of pathology, chronic T. muris infection is associated with upregulation of IL-10R and SOCS3 in addition to IL-10 and IFN-γ in the intestine (126,193).…”