A Live and Inactivated<i>Chlamydia trachomatis</i>Mouse Pneumonitis Strain Induces the Maturation of Dendritic Cells That Are Phenotypically and Immunologically Distinct

Respiratory failure during Pneumocystis pneumonia is mainly a consequence of exaggerated inflammatory responses to the organism. Dendritic cells (DCs) are the most potent APCs in the lung and are key to the regulation of innate and adaptive immune responses. However, their participation in the inflammatory response directed against Pneumocystis infection has not been fully elucidated. Therefore, we studied the role of Pneumocystis carinii, as well as Saccharomyces cerevisiae, cell wall-derived β-glucans, in DC costimulatory molecule expression. We further studied the impact of β-glucans on subsequent T cell activation. Because cytokine secretion by DCs has recently been shown to be regulated by Fas ligand (FasL), its role in β-glucan activation of DCs was also investigated. β-Glucan-induced DC activation occurred in part through dectin-1 receptors. We demonstrated that DC activation by β-glucans elicits T cell activation and polarization into a Th1 patterned response, but with the conspicuous absence of IL-12. These observations differed from LPS-driven T cell polarization, suggesting that β-glucans and LPS signal DC activation through different mechanisms. We additionally determined that IL-1β and TNF-α secretion by β-glucan-stimulated DCs was partially regulated by Fas-FasL. This suggests that dysregulation of FasL could further enhance exuberant and prolonged cytokine production by DCs following DC-T cell interactions, further promoting lung inflammation typical of Pneumocystis pneumonia.

Section: Pneumocystis Cell Wall ␤-Glucans Induce Costimulatory Molecumentioning

confidence: 97%

PneumocystisCell Wall β-Glucans Induce Dendritic Cell Costimulatory Molecule Expression and Inflammatory Activation through a Fas-Fas Ligand Mechanism

Carmona

Vassallo

Vuk-Pavlović

et al. 2006

“…with Chlamydia (14) or naive mice using MACS CD4 T cell isolation kit (Miltenyi Biotec). CD4 T cells of Ͼ90% purity were obtained as measured by FACS (data not shown).…”

Section: Elisamentioning

confidence: 99%

“…Our previous work has demonstrated that expression of GM-CSF (a cytokine known to mobilize DCs) in the mouse airway significantly enhanced systemic Th1 cellular immune responses following mucosal immunization with inactivated Chlamydia muridarum (13). Subsequent in vitro observations demonstrated that DCs exposed to live or to UV-irradiated C. muridarum develop distinct phenotypes, such that DCs exposed to live Chlamydia become mature and effectively present Ag to Chlamydia-specific CD4 T cells, while DCs exposed to UV-irradiated Chlamydia were less immunologically mature (14). Using GeneChip microarrays we observed that 33 genes were differentially expressed in response to live vs UV-irradiated Chlamydia, including three neutrophil chemoattractant chemokines, KC, MIP-2, and LIX (15).…”

mentioning

confidence: 99%

Immunoproteomic Discovery of Novel T Cell Antigens from the Obligate Intracellular PathogenChlamydia

Karunakaran

Rey-Ladino

Stoynov

et al. 2008

Self Cite

*Chlamydia infections cause substantial morbidity worldwide and effective prevention will depend on a vaccine. Since Chlamydia immunity is T cell-mediated, a major impediment to developing a molecular vaccine has been the difficulty in identifying relevant T cell Ags. In this study, we used a combination of affinity chromatography and tandem mass spectrometry to identify 13 Chlamydia peptides among 331 self-peptides presented by MHC class II (I-A b ) molecules from bone marrow-derived murine dendritic cells infected with Chlamydia muridarum. These MHC class II-bound peptides were recognized by Chlamydia-specific CD4 T cells harvested from immune mice and adoptive transfer of dendritic cells pulsed ex vivo with the peptides partially protected mice against intranasal and genital tract Chlamydia infection. The results provide evidence for lead vaccine candidates for a T cell-based subunit molecular vaccine against Chlamydia infection suitable for human study. The Journal of Immunology, 2008, 180: 2459 -2465. W orld-wide Chlamydia trachomatis is annually responsible for Ͼ92 million sexually transmitted infections and 85 million ocular infections (1). Public health programs have targeted C. trachomatis as a major problem because the organism causes long-term sequelae such as infertility, ectopic pregnancy, and blindness. Sexually transmitted C. trachomatis is also a potent cofactor facilitating the transmission of HIV (2) and interacts with oncogenic human papilloma virus in the pathogenesis of cervical neoplasia (3). In developed countries, public health measures to control Chlamydia are failing as case rates continue to rise, perhaps due to early antibiotic treatment interfering with the acquisition of immunity (4); these approaches to control Chlamydia are not feasible for much of the developing world. Thus, a new approach, such as an effective vaccine, is needed if Chlamydia control is to be achieved in the developing and developed world.Previous vaccine research using inactivated Chlamydia bacterial cells demonstrated partial short-term protection which may have been complicated by immunopathology during breakthrough infection (5). These vaccine trials yielded important lessons for the modern era of Chlamydia vaccinology, namely, that an effective Chlamydia vaccine will need to be molecularly defined and engender long-lived protective immune responses. Immunity to C. trachomatis is now known to depend on cell-mediated immune (CMI) 3 responses, especially Th1-polarized cytokine responses (6). Abs appear to play a secondary role (7). Experience has shown that developing vaccines for intracellular pathogens that require protective CMI is more difficult than for pathogens that simply require protective Ab (8). Part of the problem has been the identification of Ags that induce CMI responses because such Ags need to be presented to T cells by MHC molecules, and identifying MHC-bound microbial epitopes has been notoriously difficult (6). Since T cell responses mainly recognize protein Ags, protective vaccine candida...

“…A recent study showed that NK cells can enhance the capacity of DC to present parasitic Ags via the NKG2D receptor pathway (21). The important role of DC in initiation and maintenance of T cell responses to chlamydial infection has been demonstrated by several previous studies using mouse models of C. trachomatis mouse pneumonitis strain, more recently called Chlamydia muridarum (22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Su et al (22) reported that i.v.…”

mentioning

confidence: 99%

“…In contrast, by comparing DC from wildtype and IL-10 gene knockout mice, He et al (30) found that IL-10 production by DC was associated with inhibition of Th1 immunity to chlamydial infection. Moreover, Rey-Ladino et al (31) reported that DC with distinct phenotype and cytokine production patterns are different in immunogenicity.…”

mentioning

confidence: 99%

NK Cells Promote Type 1 T Cell Immunity through Modulating the Function of Dendritic Cells during Intracellular Bacterial Infection

Jiao

Gao

Joyee

et al. 2011

Dendritic cells (DC) play a key role in establishing protective adaptive immunity in intracellular bacterial infections, but the cells influencing DC function in vivo remain unclear. In this study, we investigated the role of NK cells in modulating the function of DC using a murine Chlamydia infection model. We found that the NK cell-depleted mice showed exacerbated disease after respiratory tract Chlamydia muridarum infection, which was correlated with altered T cell cytokine profile. Furthermore, DC from C. muridarum-infected NK-depleted mice (NK−DC) exhibited a less mature phenotype compared with that of DC from the infected mice without NK depletion (NK+DC). NK−DC produced significantly lower levels of both IL-12 and IL-10 than those of NK+DC. Moreover, NK−DC showed reduced ability to direct primary and established Ag-specific Th1 CD4+ T cell responses in DC–T coculture systems. More importantly, adoptive transfer of NK−DC, in contrast to NK+DC, failed to induce type 1 protective immunity in recipients after challenge infection. Finally, NK cells showed strong direct enhancing effect on IL-12 production by DC in an NK–DC coculture system, which was partially reduced by blocking NKG2D receptors signaling and virtually abolished by neutralizing IFN-γ activity. The data demonstrate a critical role of NK cells in modulating DC function in an intracellular bacterial infection.