Chlamydia pneumoniae Infection Induced Allergic Airway Sensitization Is Controlled by Regulatory T-Cells and Plasmacytoid Dendritic Cells

Timothy R Crother,Anatoly Slepenkin,Shuang Chen,Nicolas W J Schröder,Randa Alsabeh,Kenichi Shimada,Justin Karlin,Moshe Arditi,Ellena Peterson,Deepak Kaushal

doi:10.1371/journal.pone.0020784

Abstract

Chlamydia pneumoniae (CP) is associated with induction and exacerbation of asthma. CP infection can induce allergic airway sensitization in mice in a dose- and time-dependent manner. Allergen exposure 5 days after a low dose (mild-moderate), but not a high dose (severe) CP infection induces antigen sensitization in mice. Innate immune signals play a critical role in controlling CP infection induced allergic airway sensitization, however these mechanisms have not been fully elucidated. Wild-type, TLR2−/−, and TLR4−/− mice were infected intranasally (i.n.) with a low dose of CP, followed by i.n. exposure to human serum albumin (HSA) and challenged with HSA 2 weeks later. Airway inflammation, immunoglobulins, eosinophils, and goblet cells were measured. Low dose CP infection induced allergic sensitization in TLR2−/− mice, but not in TLR4−/− mice, due to differential Treg responses in these genotypes. TLR2−/− mice had reduced numbers of Tregs in the lung during CP infection while TLR4−/− mice had increased numbers. High dose CP infection resulted in an increase in Tregs and pDCs in lungs, which prevented antigen sensitization in WT mice. Depletion of Tregs or pDCs resulted in allergic airway sensitization. We conclude that Tregs and pDCs are critical determinants regulating CP infection-induced allergic sensitization. Furthermore, TLR2 and TLR4 signaling during CP infection may play a regulatory role through the modulation of Tregs.

Highlights

Asthma is characterized by an inappropriate immune response that results in bronchoconstriction, mucus secretion, and eosinophilic airway inflammation, and is thought to develop in two stages [1]
Murine studies showed that a mild pulmonary Chlamydia pneumoniae (CP) infection could act as an adjuvant for antigen sensitization to an otherwise inert protein (human serum albumin (HSA)), which upon re-exposure to HSA resulted in eosinophilic airway inflammation and goblet cell hyperplasia [10]
In order to dissect the molecular mechanisms as to why TLR22/2 mice but not TLR42/2 mice could be sensitized, we investigated the relative activation of TLR22/2 and TLR42/2 bone marrow derived dendritic cells (BMDCs) by CP infection

Summary

Introduction

Asthma is characterized by an inappropriate immune response that results in bronchoconstriction, mucus secretion, and eosinophilic airway inflammation, and is thought to develop in two stages [1]. The first stage, known as sensitization, encompasses the exposure to a normally innocuous antigen in the lungs during some type of inflammatory response that leads to the development of Th2 type memory cells [2]. Experimental studies using murine models have shown that pulmonary viral infections can enhance antigen sensitization and or lead to exacerbation of asthma, depending on the timing and severity of infection [4,5]. Murine studies showed that a mild pulmonary CP infection could act as an adjuvant for antigen sensitization to an otherwise inert protein (human serum albumin (HSA)), which upon re-exposure to HSA resulted in eosinophilic airway inflammation and goblet cell hyperplasia [10]. Temporal and doserelated effects on the ability of CP infection to induce allergic sensitization reflected DC activation and could be reproduced by means of adoptive transfer of HSA-pulsed lung DCs from infected mice, and be modulated by Treg cells [10]

Methods

Results

Conclusion