Gastroenterology

Gastroenterology

Volume 136, Issue 1, January 2009, Pages 257-267
Gastroenterology

Basic—Alimentary Tract
RORγ-Expressing Th17 Cells Induce Murine Chronic Intestinal Inflammation via Redundant Effects of IL-17A and IL-17F

https://doi.org/10.1053/j.gastro.2008.10.018Get rights and content

Background and Aims

IL-17–producing CD4+ T-helper cells (Th17) contribute to chronic autoimmune inflammation in the brain, and levels of Th17-derived cytokines increase in patients with colitis, suggesting a role in pathogenesis. We analyzed the roles of Th17 cells and the transcription factor retinoic acid receptor-related organ receptor (ROR)γ, which regulates Th17 differentiation, in chronic intestinal inflammation.

Methods

Using an adoptive transfer model of colitis, we compared the colitogenic potential of wild-type, interleukin-17A (IL-17A)–, IL-17F–, IL-22–, and RORγ-deficient CD4+CD25 T cells in RAG1-null mice.

Results

Adoptive transfer of IL-17A–, IL-17F–, or IL-22–deficient T lymphocytes into RAG1-null mice caused severe colitis that was indistinguishable from that caused by wild-type cells. In contrast, transfer of RORγ-null T cells failed to increase mucosal IL-17 cytokine levels and did not induce colitis. Treatment with IL-17A was able to restore colitis after transfer of RORγ-null T cells, indicating a crucial role for Th17 cells in pathogenesis. Treatment of RAG1 mice that received IL-17F–null (but not wild-type) T cells with a neutralizing anti–IL-17A antibody significantly suppressed disease, indicating redundant biological effects of IL-17A and IL-17F.

Conclusions

We have identified a crucial role of RORγ-expressing Th17 cells in chronic intestinal inflammation. RORγ controls IL-17A and IL-17F production, and these cytokines have a redundant but highly pathogenic role in gut inflammation. Reagents that target RORγ or a combination of anti–IL-17A and anti–IL-17F might be developed as therapeutics for chronic colitis.

Section snippets

Mice

IL-17A−/−, IL-22−/−, and IL-17F−/− mice were provided by Regeneron Pharmaceuticals (Tarrytown, NY) and Merck Serono (Geneva, Switzerland), respectively. All mice were on a C57BL/6 background. Wild-type littermates were used as controls. RAG1−/− mice, aged 6 to 12 weeks, were obtained from the animal facility of the University of Mainz. All mice were kept under specific pathogen-free conditions, and all experiments were performed in agreement with local regulations.

Isolation and Culture of Primary Cells

CD4+CD25 T cells were

T Cell–Dependent Experimental Colitis Is Not Affected by IL-17A Deficiency

To address the role of Th17 cells in the pathogenesis of colitis, we took advantage of an adoptive transfer model, in which CD4+CD25 T cells are introduced into T cell– and B cell–deficient RAG1−/− hosts (Figure 1A). The adoptive transfer model of colitis is characterized by a severe T cell–dependent colitis with mucosal infiltration of immune cells, chronic diarrhea, and weight loss.19 We hypothesized that Th17 cells and their hallmark cytokine IL-17A might play an important role in the

Discussion

The role of Th17 cells in chronic intestinal inflammation has recently been under debate.23, 24, 25, 26, 27, 28 While the potential relevance of Th17 cells has been highlighted by the finding that Th17 cells accumulate in the mesenteric lymph nodes and colonic lamina propria in T-cell transfer colitis,24 recent studies demonstrated that IL-17A production by T cells is not essential to induce such chronic T cell–dependent colitis.23, 28 However, IL-23, a heterodimeric cytokine that drives Th17

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    M.L. and C.B. contributed equally to this work. D.R.L. and M.F.N. share senior authorship.

    The authors disclose the following: The research of M.F.N. was supported by the MAIFOR program of the University of Mainz and the Collaborative Research Centers SFB548 and SFB432 of the German Research Council (DFG). M.L. was supported by the research training group GK 1043/1 of the German Research Council (DFG) and the Studienstiftung des deutschen Volkes. I.I.I. was supported by a fellowship from the Crohn's and Colitis Foundation of America.

    Authors affiliated with either Regeneron Pharmaceuticals or Merck Serono International are employees and stockholders of the respective companies. All other authors do not have any financial conflict of interest.

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