CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis

Abstract

Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumor necrosis factor α (TNFα) levels associated with reduced infiltration of inflammatory immune cells to sites of inflammation. Although neutralization of TNFα prevented the onset of colitis, anti-TNFα treatment of mice with established disease failed to resolve colonic inflammation. Collectively, this new model of reversible colitis provides an important research tool to study the dynamics of mucosal healing in chronic intestinal remitting-relapsing disorders.

Divergent Roles of Interferon-γ and Innate Lymphoid Cells in Innate and Adaptive Immune Cell-Mediated Intestinal Inflammation

“…Although IFNγ has been associated with IBD and experimental models of intestinal inflammation, its role in disease pathogenesis remains controversial. Such controversies may be the result of the mode of disease induction, distinct disease kinetics, genetic background, or variability in the gut commensal community structure in the different vivaria ( 18 , 19 ). Here, we tested the role for IFNγ in two well-established models of intestinal inflammation in microbiota-stabilized hosts.…”

“…To this end, naive CD4 CD45RB hi T cells from IFNγ-sufficient ( Ifng +/+ ) or IFNγ-deficient mice ( Ifng −/−) were adoptively transferred into lymphopenic IFNγ sufficient ( Rag1 −/− Ifng +/+ ) or deficient hosts ( Rag1 −/− Ifng −/− ). CD4 T cell expansion in peripheral blood as a sign of colitis onset ( 19 ) and body weight were monitored throughout the experiment. Both, IFNγ-sufficient and - deficient mice developed comparable histopathological changes in the colonic mucosa in response to adaptive CD4 T cell transfers associated with 10–15% weight loss of initial body weight (Figures 1 D–F).…”

The ESRP1-GPR137 axis contributes to intestinal pathogenesis

“…Intestinal inflammation was assessed in a single blinded manner on H&E-stained tissue sections by a board-certified pathologist (V.G. ), as previously described ( Brasseit et al, 2016 ). Clinical disease activity was quantified as follows: Weight loss, compared to initial weight (Score 0, <1% weight loss; score 1, 1–5% weight loss; score 2, 5–15% weight loss; score 4, 15–20% or more weight loss); Stool consistency (Score 0, normal stool; score 2, loose stool; score 4, diarrhea); Intestinal bleeding (Score 0, negative; score 2, positive).…”

Other Helicobacters and gastric microbiota

“…H. hepaticus‐ or H. typhlonius ‐infected mice are frequently used as a model for a better understanding of the pathogenesis of inflammatory bowel diseases in humans. IL‐23 produced by monocytes, IL‐17 and IL‐22 produced by Th17 cells, IFNγ and IL‐17 produced by Th1/17 cells, and TNFα produced by colitogenic T cells seem to be associated with the development of intestinal inflammation. Ray et al .…”