Interruption of CXCL13-CXCR5 Axis Increases Upper Genital Tract Pathology and Activation of NKT Cells following Chlamydial Genital Infection

Abstract

BackgroundRegulation of immune responses is critical for controlling inflammation and disruption of this process can lead to tissue damage. We reported that CXCL13 was induced in fallopian tube tissue following C. trachomatis infection. Here, we examined the influence of the CXCL13-CXCR5 axis in chlamydial genital infection.Methodology and Principal FindingsDisruption of the CXCL13-CXCR5 axis by injecting anti-CXCL13 Ab to BALB/c mice or using Cxcr5−/− mice increased chronic inflammation in the upper genital tract (UGT; uterine horns and oviducts) after Chlamydia muridarum genital infection (GT). Further studies in Cxcr5−/− mice showed an elevation in bacterial burden in the GT and increased numbers of neutrophils, activated DCs and activated NKT cells early after infection. After resolution, we noted increased fibrosis and the accumulation of a variety of T cells subsets (CD4-IFNγ, CD4-IL-17, CD4-IL-10 & CD8-TNFα) in the oviducts. NKT cell depletion in vitro reduced IL-17α and various cytokines and chemokines, suggesting that activated NKT cells modulate neutrophils and DCs through cytokine/chemokine secretion. Further, chlamydial glycolipids directly activated two distinct types of NKT cell hybridomas in a cell-free CD1d presentation assay and genital infection of Cd1d−/− mice showed reduced oviduct inflammation compared to WT mice. CXCR5 involvement in pathology was also noted using single-nucleotide polymorphism analysis in C. trachomatis infected women attending a sub-fertility clinic. Women who developed tubal pathology after a C. trachomatis infection had a decrease in the frequency of CXCR5 SNP +10950 T>C (rs3922).Conclusions/SignificanceThese experiments indicate that disruption of the CXCL13-CXCR5 axis permits increased activation of NKT cells by type I and type II glycolipids of Chlamydia muridarum and results in UGT pathology potentially through increased numbers of neutrophils and T cell subsets associated with UGT pathology. In addition, CXCR5 appears to contribute to inter-individual differences in human tubal pathology following C. trachomatis infection.

<b><i>Chlamydia trachomatis</i></b> Infections and Subfertility: Opportunities to Translate Host Pathogen Genomic Data into Public Health

“…Thus, inflammation associated with CCR5 may predispose to development of complications of C. trachomatis infection. Recent findings show a similar pattern for CXCR5 [49]. …”

Invariant Natural Killer T Cells: Boon or Bane in Immunity to Intracellular Bacterial Infections?

“…The GLXA activated the cells to express higher levels of the activation marker CD69, and enhanced the production of IFN-γ and IL-4 in vivo [9]. In accordance with these findings, Jiang et al [38 ]showed that sonicated C. muridarum activated iNKT and type 2 NKT cells in an antigen-presenting cell-free culture system coated with CD1d molecules and with the use of iNKT or type 2 NKT cell hybridomas. Since the ligands of type 2 NKT cells and iNKT cells are different [58,59], it is likely that C. muridarum contains different kinds of lipid antigens for these NKT cell types.…”

“…Further analysis of immune response in the KO mice showed reduced T H 2 responses [19,37]. Consistently, when subjected to a C. muridarum infection of the genital tract, CD1d-KO mice showed reduced pathological changes in the oviduct [38]. The comparison of the iNKT cells in C. pneumoniae and C. muridarum infections has revealed distinct cytokine patterns, i.e.…”

From the Deep Sea to Everywhere: Environmental Antigens for iNKT Cells

“…iNKT cell antigen in pathogenic bacteria has also been proposed for Leishmania donovani (Amprey et al 2004;Karmakar et al 2011) and Chlamydia muridarum (Jiang et al 2012;Peng et al 2012). …”