Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jun 1;186(11):6313-8.
doi: 10.4049/jimmunol.1001454. Epub 2011 Apr 29.

Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production

Ting Feng  1 , Hongwei Qin, Lanfang Wang, Etty N Benveniste, Charles O Elson, Yingzi Cong
Affiliations

Th17 cells induce colitis and promote Th1 cell responses through IL-17 induction of innate IL-12 and IL-23 production

Ting Feng et al. J Immunol. .

Abstract

Both Th1 and Th17 cells have been implicated in the pathogenesis of inflammatory bowel disease and experimental colitis. However, the complex relationship between Th1 and Th17 cells and their relative contributions to the pathogenesis of inflammatory bowel disease have not been completely analyzed. Although it has been recently shown that Th17 cells can convert into Th1 cells, the underlying in vivo mechanisms and the role of Th1 cells converted from Th17 cells in the pathogenesis of colitis are still largely unknown. In this study, we report that Th17 cells from CBir1 TCR transgenic mice, which are specific for an immunodominant microbiota Ag, are more potent than Th1 cells in the induction of colitis, as Th17 cells induced severe colitis, whereas Th1 cells induced mild colitis when transferred into TCRβxδ(-/-) mice. High levels of IL-12 and IL-23 and substantial numbers of IFN-γ(+) Th1 cells emerged in the colons of Th17 cell recipients. Administration of anti-IL-17 mAb abrogated Th17 cell-induced colitis development, blocked colonic IL-12 and IL-23 production, and inhibited IFN-γ(+) Th1 cell induction. IL-17 promoted dendritic cell production of IL-12 and IL-23. Furthermore, conditioned media from colonic tissues of colitic Th17 cell recipients induced IFN-γ production by Th17 cells, which was inhibited by blockade of IL-12 and IL-23. Collectively, these data indicate that Th17 cells convert to Th1 cells through IL-17 induction of mucosal innate IL-12 and IL-23 production.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Naïve CBir1 Tg T cells differentiate into both Th1 and Th17 cells in the intestine and induce colitis in TCRβxδ−/− mice
1 × 106 CBir1 Tg CD4+ T cells were transferred into TCRβxδ−/− mice. A groups of 5 TCRβxδ−/− mice were injected with PBS as control. The recipients were sacrificed at different time points. A, Lamina propria (LP) CD4+ T cell intracellular IFNγ and IL-17 production was determined by flow cytometry. Plot numbers represent the percentage of CD4 positive T cells in the respective quadrants. B, Absolute numbers of IFNγ+ and IL-17+ CD4+ T cells in MLN and LP. C, Aggregate data of percentages of LP IFNγ+ and IL-17+ T cells from three independent experiments. D, Colonic histopathology was assessed at different time points after cell transfer. Pathology scores are shown. **p < 0.01. One representative of three independent experiments is shown.
Figure 2
Figure 2. CBir1 Tg Th17 cells are more potent than Th1 cells in the induction of colitis
To determine the ability of Th17 and Th1 cells to induce colitis, CBir1 Tg Th17 and Th1 cells were polarized in vitro under standard Th17 and Th1 conditions (A), and 1 × 106 Th17 and Th1 cells were transferred into groups of 5 TCRβxδ−/− mice separately. Eight weeks after transfer, the recipient mice were sacrificed and assessed for histopathology. Colonic histopathology (B) and pathology scores (C) are shown. **p < 0.01. D, Absolute numbers of CD4+ T cells in MLN and LP are shown. *p < 0.01. Data are one representative of three independent experiments.
Figure 3
Figure 3. IL-17 mediates CBir1-specific Th17 cell conversion to Th1 cells and induction of colitis in TCRβxδ−/− mice
1 × 106 in vitro-polarized CBir1 Tg Th17 cells (A) were transferred into TCRβxδ−/− mice. Groups of 5 recipient mice were administered with 100 µg/mouse of anti-IL-17 mAb or control mAb at the time of transfer and weekly thereafter. Eight weeks after transfer, the mice were sacrificed. Absolute numbers of CD4+ T cells were counted in MLN and LP (B), and LP CD4+ T cell IFNγ and IL-17 production was determined by flow cytometry (C). Plot numbers represent the percentage of CD4 positive T cells in the respective quadrants. *p < 0.01 compared to control mAb-treated group. To determine local mucosal cytokine production, colonic tissues of Th17 recipient mice were cultured for 24 h, and production of IFNγ and IL-17 in the supernatants was determined by ELISA (D). *p < 0.01 compared to control mAb-treated group. The colonic histopathology was assessed. Pathology scores (E) and colonic histopathology (F) are shown. **p < 0.01 compared to control mAb-treated group. Data are one representative of two independent experiments.
Figure 4
Figure 4. IL-17 mediates Th17 cell induction of colonic IL-12 and IL-23 in vivo and stimulates DC IL-12 and IL-23 production in vitro
A, 1 × 106 in vitro-polarized CBir1 Tg Th17 cells were transferred into TCRβxδ−/− mice that were administered with anti-IL-17 mAb or control mAb at the time of transfer and weekly thereafter for eight weeks. Colonic tissues of Th17 recipients were cultured for 24 h, and IL-23 and IL-12 production in the supernatants was measured by ELISA. **p < 0.01 compared to control mAb-treated group. One representative of two independent experiments is shown. B, To determine the effect of IL-17 on BMDC IL-12 and IL-23 production, 1 × 106 cells/ml of BMDC were stimulated with IL-17 (100 ng/ml). Supernatants were collected 24 h later, and IL-12 and IL-23 levels were determined by ELISA. *p < 0.05; **p < 0.01 compared to IL-17-treated BMDC. C, BMDC were also harvested at different time points after treatment, and IL-12 and IL-23 mRNA expression was determined by RT-PCR. Data are one representative of two independent experiments with similar results. D, Aggregate data of density from two independent experiments.
Figure 5
Figure 5. Conditioned media from colonic tissues of colitic Th17 recipients induce Th17 cell conversion to Th1 cells through IL-12 and IL-23 production
A, Colonic tissues of colitic Th17 cell recipient mice were cultured in complete RPMI, and the culture supernatants were collected after 24 h to serve as “conditioned media” (CM). In vitro-polarized CBir1 Th17 cells were restimulated with CBir1 flagellin-pulsed APC in the absence or presence of 20% colonic CM with anti-IL-12, anti-IL-23, or both. Five days later, IL-17 and IFNγ production was assessed by intracellular staining. One representative of three independent experiments is shown. B, Aggregate data of percentages of cytokine-expressing T cells from three independent experiments. *p < 0.05; **p < 0.01 compared to CM-treated group.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Powrie F, Leach MW, Mauze S, Menon S, Caddle LB, Coffman RL. Inhibition of Th1 responses prevents inflammatory bowel disease in scid mice reconstituted with CD45RBhi CD4+ T cells. Immunity. 1994;1:553–562. - PubMed
    1. Berg DJ, Davidson N, Kuhn R, Muller W, Menon S, Holland G, Thompson-Snipes L, Leach MW, Rennick D. Enterocolitis and colon cancer in interleukin-10-deficient mice are associated with aberrant cytokine production and CD4(+) TH1-like responses. J Clin Invest. 1996;98:1010–1020. - PMC - PubMed
    1. Fuss IJ, Neurath M, Boirivant M, Klein JS, de la Motte C, Strong SA, Fiocchi C, Strober W. Disparate CD4+ lamina propria (LP) lymphokine secretion profiles in inflammatory bowel disease. Crohn's disease LP cells manifest increased secretion of IFN-gamma, whereas ulcerative colitis LP cells manifest increased secretion of IL-5. J Immunol. 1996;157:1261–1270. - PubMed
    1. Yen D, Cheung J, Scheerens H, Poulet F, McClanahan T, McKenzie B, Kleinschek MA, Owyang A, Mattson J, Blumenschein W, Murphy E, Sathe M, Cua DJ, Kastelein RA, Rennick D. IL-23 is essential for T cell-mediated colitis and promotes inflammation via IL-17 and IL-6. J Clin Invest. 2006;116:1310–1316. - PMC - PubMed
    1. Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, Kastelein RA. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007;132:2359–2370. - PubMed

Publication types

MeSH terms