T-bet−/− RAG2−/− ulcerative colitis: The role of T-bet as a peacekeeper of host–commensal relationships

doi:10.1016/j.cyto.2009.07.007

Cytokine

Volume 48, Issues 1–2, October–November 2009, Pages 144-147

https://doi.org/10.1016/j.cyto.2009.07.007 Get rights and content

Abstract

Inflammatory bowel disease is a disease that reflects a disequilibrium in host–commensal homeostasis. T-bet−/− × RAG2−/− deficient mice develop a spontaneous juvenile ulcerative colitis resulting from a pro-inflammatory response to the commensal microbiota that is dendritic cell and TNF-α driven [schematized in Fig. 1]. The TRUC (T-bet−/− RAG2−/− ulcerative colitis) model is discussed in the broader context of the adaptive and innate immune mechanisms that regulate host–commensal relationships within the intestine.

Introduction

Upwards of 4 million people are afflicted by inflammatory bowel disease (IBD), a spectrum of chronic illnesses driven by inflammation that can occur in the small and large intestine. Several recent genome wide association studies of human populations and multiple spontaneous and inducible mouse models have shed light on the molecular pathogenesis of these diseases and as a result are improving the therapeutic armamentarium available to treat them [1], [2]. Over 6 billion people populate this world and 99.94% of them are spared from IBD. The relatively low incidence of these diseases is in many ways astonishing considering that the human intestine is home to approximately 100 trillion bacterial organisms. The host immune system has evolved elaborate offensive and defensive strategies to protect itself from bacterial invaders. The intestine presents a different challenge to the immune system—a challenge of peaceful co-existence driven by metabolic needs that confer clear fitness and survival advantages. Bacteria function in efficient energy extraction of nutrients for the host, and bacterial metabolism also generates metabolic products essential for host physiology. Multiple mechanisms regulate host–commensal relations in the intestine. The three major players in this complex balancing act are the microbiota, intestinal epithelial cells, and immune cells. Our studies in T-bet−/− × RAG2−/− mice, which develop a commensal dependent ulcerative colitis driven by TNF-α, have provided us with some insight into the interactions amongst some of these cell sub-types [3].

Section snippets

The epithelial barrier

A key factor responsible for this host–commensal co-existence is the epithelial cell barrier that separates the vast numbers of the luminal microbes from the immune cellular networks embedded across the intestinal wall (reviewed in [4]). This barrier has multiple layers of fortification and is much more than a constantly self-renewing single layer of epithelial cells attached via tight junctions. A mucus layer also functions as an important part of this boundary. Intestinal mucus is arranged in

T-bet and DCs

T-bet is a T-box transcription factor first identified as the master-regulator of the CD4 T helper type 1 lineage of T cells. Over the past decade our understanding of the cellular expression patterns of T-bet and the T-bet transcriptionally-regulated universe of genes has expanded. T-bet controls the expression of numerous cytokines, chemokines, and chemokines receptors [18] and depending upon the expressing cell type, T-bet can function as either a repressor or activator of a given gene. In

IBD and DCs

DCs have emerged as key effectors in the pathogenesis of IBD (reviewed in [20]). Data from numerous mouse models are providing insights into how mucosal DCs function in intestinal health and disease. DCs function as linchpins of inflammatory responses demonstrated in the dextran sulfate sodium model of colitis, wherein deletion of dendritic cells using CD11c diphtheria toxin transgenic mice ameliorated colitis [21]. In CD40-induced colitis, Helicobacter hepaticus infection of RAG2−/− induced

Regulatory T cells and TRUC

TRUC mice lack mature T lymphocytes because of a RAG2 mutation. Since T-bet−/− mice on an immunosufficient background are free of spontaneous intestinal inflammation in our colony, we reasoned that an adaptive immune subset may actively inhibit colitis. Adoptive transfer of CD4⁺CD62L^hiCD25⁻ cells resulted in extremely moribund mice within 2 weeks of transfer stemming from robust T cell inflammatory responses superimposed on a background of chronic colonic ulceration and inflammation. Transfer of

TRUC and colitogenic microbes

TRUC colitis is antibiotic-responsive as are most mouse models of colitis; similarly, patients with IBD often experience symptomatic benefit from treatment with antibiotics such as metronidazole. TRUC mice, interestingly, appear to harbor microbes that are generally colitogenic. Specifically, we have observed the transmission of colitis from TRUC to T-bet sufficient mice in both cross-fostering experiments and experiments wherein adult TRUC mice are co-housed with RAG2−/− or wild type mice.

Summary

TRUC colitis is ameliorated by antibiotics, T-regulatory cell infusion, and TNF-α neutralization and thus TRUC mice provide a useful model for interrogating and evaluating the mechanisms by which these modalities ameliorate intestinal inflammation [schematized in Fig. 1]. Our studies of TRUC pathogenesis and the prominent role of DCs therein furnish additional evidence of the importance of dendritic cells in IBD. RAG2−/− deficiency, as discussed above, confers several disadvantages on TRUC mice

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Review ArticleT-bet−/− RAG2−/− ulcerative colitis: The role of T-bet as a peacekeeper of host–commensal relationships

Abstract

Introduction

Section snippets

The epithelial barrier

T-bet and DCs

IBD and DCs

Regulatory T cells and TRUC

TRUC and colitogenic microbes

Summary

Best Pract Res Clin Gastroenterol

Cell

Gastroenterology

J Biol Chem

Mucosal Immunol

Immunity

Cell Host Microbe

Immunity

Immunity

Cell Host Microbe

Cell Host Microbe

Animal models of inflammatory bowel disease at the dawn of the new genetics era

PLoS Med

Do symbiotic bacteria subvert host immunity?

Nat Rev Microbiol

The inner of the two Muc2 mucin-dependent mucus layers in colon is devoid of bacteria

Proc Natl Acad Sci USA

Multi-layered regulation of intestinal antimicrobial defense

Cell Mol Life Sci

Defensins and inflammation: the role of defensins in inflammatory bowel disease

J Gastroenterol Hepatol

Cathelicidins, multifunctional peptides of the innate immunity

J Leukoc Biol

MyD88-mediated signals induce the bactericidal lectin RegIII gamma and protect mice against intestinal Listeria monocytogenes infection

J Exp Med

Symbiotic bacteria direct expression of an intestinal bactericidal lectin

Science

Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue

J Exp Med

Critical roles of activation-induced cytidine deaminase in the homeostasis of gut flora

Science

Review Article
T-bet−/− RAG2−/− ulcerative colitis: The role of T-bet as a peacekeeper of host–commensal relationships