Th17-cell plasticity in Helicobacter hepaticus–induced intestinal inflammation

Abstract

Bacterial-induced intestinal inflammation is crucially dependent on interleukin (IL)-23 and is associated with CD4(+) T helper type 1 (Th1) and Th17 responses. However, the relative contributions of these subsets during the induction and resolution of colitis in T-cell-sufficient hosts remain unknown. We report that Helicobacter hepaticus-induced typhlocolitis in specific pathogen-free IL-10(-/-) mice is associated with elevated frequencies and numbers of large intestinal interferon (IFN)-γ(+) and IFN-γ(+)IL-17A(+) CD4(+) T cells. By assessing histone modifications and transcript levels in IFN-γ(+), IFN-γ(+)IL-17A(+), and IL-17A(+) CD4(+) T cells isolated from the inflamed intestine, we show that Th17 cells are predisposed to upregulate the Th1 program and that they express IL-23R but not IL-12R. Using IL-17A fate-reporter mice, we further demonstrate that H. hepaticus infection gives rise to Th17 cells that extinguish IL-17A secretion and turn on IFN-γ within 10 days post bacterial inoculation. Together, our results suggest that bacterial-induced Th17 cells arising in disease-susceptible hosts contribute to intestinal pathology by switching phenotype, transitioning via an IFN-γ(+)IL-17A(+) stage, to become IFN-γ(+) ex-Th17 cells.

NovelHelicobacterspeciesH.japonicumisolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10−/−mice

“…Helicobacter hepaticus infection gave rise to TH17 cells that induced IL17A secretion and elicited IFN-γ induction; both of which contributed to intestinal pathology (41). It also has been suggested recently that IL-17A can trigger gastrointestinal tumor development (42).…”

Differential Requirements for IL-17A and IL-22 in Cecal versus Colonic Inflammation Induced by Helicobacter hepaticus

“…27,28 The development of intestinal pathology after H. hepaticus inoculation is dependent on IL-23 and is associated with up-regulated Th1-and Th17-type cytokine mRNA levels as well as enhanced frequencies and numbers of cecal and colonic lamina propria (LP) CD4 þ T cells expressing IFN-g, IL-17A, IL-17F, and/or IL-22. 28,29 Interestingly, IFN-g was shown to be necessary for maximal pathology in the colon, but not in the cecum in this model, 28 suggesting regional differences in cytokine requirements for disease pathogenesis. The role of Th17-type cytokines in cecal versus colonic inflammation in H. hepaticuseinduced T-celledependent intestinal pathology has, however, not been examined.…”

“…In general, mRNA accumulation of Il17a, Il22, and Ifng was higher in the cecum than in the colon of H. hepaticuseinfected antieIL-10Retreated WT mice (Figure 2A), a pattern seen also at day 14 pi (Figure 2B) when H. hepaticuseinduced inflammation and the number of cytokine-secreting CD4 þ T cells reach their peak in the large intestine. 29 Moreover, when examining cytokine expression at the protein level, the proportion of total LP cells able to secrete IL-17A, IL-22, and IFN-g in H. hepaticuseinfected antieIL-10Retreated WT mice was higher in the cecum than in the colon at both days 14 and 21 pi ( Figure 2C). The frequency of LP cells producing these cytokines was higher in the cecum than in the colon also in uninfected controls and in WT mice given H. hepaticus alone, although the percentages were lower in these groups than in inflamed hosts ( Figure 2C).…”

“…This time period was chosen to capture the early kinetics of H. hepaticuseinduced typhlocolitis, where visible inflammation is detected by day 7 after H. hepaticus inoculation. 29 Compared with uninfected animals, WT mice given H. hepaticus alone showed minimal induction of Il17a and Il22 transcripts in the large intestine (Figure 2A). In contrast, animals given H. hepaticus plus antieIL-10R displayed enhanced mRNA accumulation of Il17a and Il22 from day 6 and day 4 pi, respectively, in both the cecum and colon, reaching significance by day 6 to 8 pi (Figure 2A).…”

Pathogenesis of Crohn’s disease: Bug or no bug

“…Other Helicobacter species, like Helicobacter hepaticus, have shown their capability of inducing colitis in animals, mainly in immunocompromised ones. Studies need to be done to see if the same effect is seen in humans [9,66,67] .…”