A transient breach in the epithelial barrier leads to regulatory T-cell generation and resistance to experimental colitis.

Abstract

BACKGROUND & AIMS:

Previous studies have indicated that a defective epithelial barrier leads to inflammation of the underlying lamina propria. Nevertheless, it is likely that physiologic breaks in the barrier must occur for homeostatic regulatory T cells to develop. We determined the effect of agents that disrupt epithelial tight junctions (ethanol and AT1002, a Vibrio cholerae zonula occludens toxin hexapeptide) on regulatory T-cell induction and resistance to induction of colitis by trinitrobenzene sulfonic acid (TNBS).

METHODS:

The effects of ethanol and AT1002 on colon immune function were evaluated by their capacity to induce direct phenotypic or functional changes in effector and regulatory cell populations and their indirect effect on the development of TNBS-induced colitis. The basis of regulatory cell development was evaluated with in vitro studies of isolated dendritic cell populations. The role of innate immunity was evaluated by in vivo gene silencing studies utilizing Toll-like receptor (TLR)-2-specific small interfering RNA (siRNA).

RESULTS:

Both ethanol and AT1002 induced persistent latency-associated peptide-positive CD4(+) regulatory T cells that, as shown in adoptive transfer studies, render mice resistant to the induction of TNBS colitis. The development of these cells requires the presence of an intact microflora and the activity of CD11c(+) dendritic cells. Their induction is also influenced by innate immune factors operating through TLR-2, because attenuation of TLR-2 signaling by in vivo TLR-2 siRNA administration prevents their development.

CONCLUSIONS:

A mild and/or transient breach in epithelial barrier function leads to dominant regulatory T-cell responses that protect the mucosa from inflammation.

• Authors: Monica Boirivant, Antonello Amendola, Alessia Butera, Massimo Sanchez, Lili Xu, Mariarosaria Marinaro, Atsushi Kitani, Claudia Di Giacinto, Warren Strober, Ivan J Fuss
• Journal: Gastroenterology (Gastroenterology) Vol. 135 Issue 5 Pg. 1612-1623.e5 (Nov 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18765239 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AT1002
• Anti-Infective Agents, Local
• Oligopeptides
• RNA, Small Interfering
• Tlr2 protein, mouse
• Toll-Like Receptor 2
• Ethanol

Topics

• Animals
• Anti-Infective Agents, Local (pharmacology)
• Blotting, Western
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Cell Membrane Permeability (drug effects)
• Cells, Cultured
• Colitis (immunology, metabolism, pathology)
• Disease Models, Animal
• Ethanol (pharmacology)
• Immunity, Cellular (physiology)
• Intestinal Mucosa (drug effects, immunology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Oligopeptides (pharmacology)
• RNA, Small Interfering (genetics)
• T-Lymphocytes, Regulatory (immunology)
• Toll-Like Receptor 2 (drug effects, genetics, metabolism)